Arylaminoalcohol-substituted 2,3-dihydroimidazo[1,2-c]quinolines

ABSTRACT

The present invention relates to substituted phenoxypyridine compounds of general formula (I); in which R 1 , R 2  and R 3  are as defined in the claims, to methods of preparing said compounds, to intermediates for the preparation of said compounds, to pharmaceutical compositions and combinations comprising said compounds and to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease, in particular of a hyper-proliferative and/or angiogenesis disorder, as a sole agent or in combination with other active ingredients.

FIELD OF THE INVENTION

The present invention relates to arylaminoalcohol-substituted2,3-dihydroimidazo[1,2-c]quinolines, (hereinafter referred to as“compounds of general formula (I)”) as described and defined herein, tomethods of preparing said compounds, to intermediates for thepreparation of said compounds, to pharmaceutical compositions andcombinations comprising said compounds and to the use of said compoundsfor manufacturing a pharmaceutical composition for the treatment orprophylaxis of a disease, in particular of a hyper-proliferative and/orangiogenesis disorder, as a sole agent or in combination with otheractive ingredients.

BACKGROUND OF THE INVENTION

In the last decade the concept of developing anti-cancer medicationswhich target abnormally active protein kinases has led to a number ofsuccesses. In addition to the actions of protein kinases, lipid kinasesalso play an important role in generating critical regulatory secondmessengers. The PI3K family of lipid kinases generates3′-phosphoinositides that bind to and activate a variety of cellulartargets, initiating a wide range of signal transduction cascades(Vanhaesebroeck et al., 2001; Toker, 2002; Pendaries et al., 2003;Downes et al., 2005). These cascades ultimately induce changes inmultiple cellular processes, including cell proliferation, cellsurvival, differentiation, vesicle trafficking, migration, andchemotaxis.

PI3Ks can be divided into three distinct classes based upon differencesin both structure, and substrate preference. While members of the ClassII family of PI3Ks have been implicated in the regulation of tumorgrowth (Brown & Shepherd, 2001; Traer et al., 2006), the bulk ofresearch has focused on the Class I enzymes and their role in cancer(Stauffer et al., 2005; Stephens et al., 2005; Vivanco & Sawyers, 2002;Workman, 2004; Chen et al., 2005; Hennessy et al., 2005; Cully et al.,2006).

Class I PI3Ks have traditionally been divided into two distinctsub-classes based upon differences in protein subunit composition. TheClass I_(A) PI3Ks are comprised of a catalytic p110 catalytic subunit(p110α, β or δ) heterodimerized with a member of the p85 regulatorysubunit family. In contrast, the Class I_(B) PI3K catalytic subunit(p110γ) heterodimerizes with a distinct p101 regulatory subunit(reviewed by Vanhaesebroeck & Waterfield, 1999; Funaki et al., 2000;Katso et al., 2001). The C-terminal region of these proteins contains acatalytic domain that possesses distant homology to protein kinases. ThePI3Kγ structure is similar to Class I_(A) p110s, but lacks theN-terminal p85 binding site (Domin & Waterfield, 1997). Though similarin overall structure, the homology between catalytic p110 subunits islow to moderate. The highest homology between the PI3K isoforms is inthe kinase pocket of the kinase domain.

The Class I_(A) PI3K isoforms associate with activated receptor tyrosinekinases (RTKs) (including PDGFR, EGFR, VEGFR, IGF1-R, c-KIT, CSF-R andMet), or with tyrosine phosphorylated adapter proteins (such as Grb2,Cbl, IRS-1 or Gab1), via their p85 regulatory subunits resulting instimulation of the lipid kinase activity. Activation of the lipid kinaseactivity of the p110β and p110γ isoforms has been shown to occur inresponse to binding to activated forms of the ras Oncogene (Kodaki etal., 1994). In fact, the oncogenic activity of these isoforms mayrequire binding to ras (Kang et al., 2006). In contrast, the p110α andp110δ isoforms exhibit oncogenic activity independent of ras binding,through constitutive activation of Akt.

Class I PI3Ks catalyze the conversion of PI(4,5)P₂ [PIP₂] to PI(3,4,5)P₃[PIP₃]. The production of PIP₃ by PI3K affects multiple signalingprocesses that regulate and coordinate the biological end points of cellproliferation, cell survival, differentiation and cell migration. PIP₃is bound by Pleckstrin-Homology (PH) domain-containing proteins,including the phosphoinositide-dependent kinase. PDK1 and the Aktproto-oncogene product, localizing these proteins in regions of activesignal transduction and also contributing directly to their activation(Klippel et al., 1997; Fleming et al., 2000; Itoh & Takenawa, 2002;Lemmon, 2003). This co-localization of PDK1 with Akt facilitates thephosphorylation and activation of Akt. Carboxy-terminal phosphorylationof Akt on Ser⁴⁷³ promotes phosphorylation of Thr³⁰⁸ in the Aktactivation loop (Chan & Tsichlis, 2001; Hodgkinson et al., 2002; Scheidet al., 2002; Hresko et al., 2003). Once active, Akt phosphorylates andregulates multiple regulatory kinases of pathways that directlyinfluence cell cycle progression and cell survival.

Many of the effects of Akt activation are mediated via its negativeregulation of pathways which impact cell survival and which are commonlydysregulated in cancer. Akt promotes tumor cell survival by regulatingcomponents of the apoptotic and cell cycle machinery. Akt is one ofseveral kinases that phosphorylate and inactivate pro-apoptotic BADproteins (del Peso et al., 1997; Pastorino et al., 1999). Akt may alsopromote cell survival through blocking cytochrome C-dependent caspaseactivation by phosphorylating Caspase 9 on Ser¹⁹⁶ (Cardone et al.,1998).

Akt impacts gene transcription on several levels. The Akt-mediatedphosphorylation of the MDM2 E3 ubiquitin ligase on Ser¹⁶⁶ and Ser¹⁸⁶facilitates the nuclear import of MDM2 and the formation and activationof the ubiquitin ligase complex. Nuclear MDM2 targets the p53 tumorsuppressor for degradation, a process that can be blocked by LY294002(Yap et al., 2000; Ogawara et al., 2002). Downregulation of p53 by MDM2negatively impacts the transcription of p53-regulated pro-apoptoticgenes (e.g. Bax, Fas, PUMA and DR5), the cell cycle inhibitor,p21^(Cip1), and the PTEN tumor suppressor (Momand et al., 2000; Hupp etal., 2000; Mayo et al., 2002; Su et al., 2003). Similarly, theAkt-mediated phosphorylation of the Forkhead transcription factors FKHR.FKHRL and AFX (Kops et al., 1999; Tang et al., 1999), facilitates theirbinding to 14-3-3 proteins and export from the cell nucleus to thecytosol (Brunet et al., 1999). This functional inactivation of Forkheadactivity also impacts pro-apoptotic and pro-angiogenic genetranscription including the transcription of Fas ligand (Ciechomska etal., 2003) Bim, a pro-apoptotic Bcl-2 family member (Dijkers et al.,2000), and the Angiopoietin-1 (Ang-1) antagonist, Ang-2 (Daly et al.,2004). Forkhead transcription factors regulate the expression of thecyclin-dependent kinase (Cdk) inhibitor p27%. Indeed. PI3K inhibitorshave been demonstrated to induce D27^(Kip1) expression resulting in Cdk1inhibition, cell cycle arrest and apoptosis (Dijkers et al., 2000). Aktis also reported to phosphorylate p21^(Cip1) on Thr¹⁴⁵ and p27^(Kip1) onThr¹⁵⁷ facilitating their association with 14-3-3 proteins, resulting innuclear export and cytoplasmic retention, preventing their inhibition ofnuclear Cdks (Zhou et al., 2001; Motti et al., 2004; Sekimoto et al.,2004). In addition to these effects, Akt phosphorylates IKK (Romashkova& Makarov, 1999), leading to the phosphorylation and degradation of IκBand subsequent nuclear translocation of NFκB, resulting in theexpression of survival genes such as IAP and Bcl-X_(L).

The PI3K/Akt pathway is also linked to the suppression of apoptosisthrough the JNK and p38^(MAPK) MAP Kinases that are associated with theinduction of apoptosis. Akt is postulated to suppress JNK and p38^(MAPK)signaling through the phosphorylation and inhibition of two JNK/p38regulatory kinases, Apoptosis Signal-regulating Kinase 1 (ASK1) (Kim etal., 2001; Liao & Hung, 2003; Yuan et al., 2003), and Mixed LineageKinase 3 (MLK3) (Lopez-Hasaca et al., 1997; Barthwal et al., 2003;Figueroa et al., 2003). The induction of p38^(MAPK) activity is observedin tumors treated with cytotoxic agents and is required for those agentsto induce cell death (reviewed in Olson & Hallahan, 2004). Thus,inhibitors of the PI3K pathway may promote the activities ofco-administered cytotoxic drugs.

An additional role for PI3K/Akt signaling involves the regulation ofcell cycle progression through modulation of Glycogen Synthase Kinase 3(GSK3) activity. GSK3 activity is elevated in quiescent cells, where itphosphorylates cyclin D₁ on Ser²⁸⁶, targeting the protein forubiquitination and degradation (Diehl et al., 1998) and blocking entryinto S-phase. Akt inhibits GSK3 activity through phosphorylation on Ser⁹(Cross et al., 1995). This results in the elevation of Cyclin D₁ levelswhich promotes cell cycle progression. Inhibition of GSK3 activity alsoimpacts cell proliferation through activation of the wnt/beta-cateninsignaling pathway (Abbosh & Nephew, 2005; Naito et al., 2005; Wilker etal., 2005; Segrelles et al., 2006). Akt mediated phosphorylation of GSK3results in stabilization and nuclear localization of the beta-cateninprotein, which in turn leads to increased expression of c-myc and cyclinD1, targets of the beta-catenin/Tcf pathway.

Although PI3K signaling is utilized by many of the signal transductionnetworks associated with both oncogenes and tumor suppressors. PI3K andits activity have been linked directly to cancer. Overexpression of boththe p110α and p110β isoforms has been observed in bladder and colontumors and cell lines, and overexpression generally correlates withincreased PI3K activity (Bénistant et al., 2000). Overexpression ofp110α has also been reported in ovarian and cervical tumors and tumorcell lines, as well as in squamous cell lung carcinomas. Theoverexpression of p110α in cervical and ovarian tumor lines isassociated with increased PI3K activity (Shayesteh et al., 1999; Ma etal., 2000). Elevated PI3K activity has been observed in colorectalcarcinomas (Phillips et al., 1998) and increased expression has beenobserved in breast carcinomas (Gershtein et al., 1999).

Over the last few years, somatic mutations in the gene encoding p110α(PIK3CA) have been identified in numerous cancers. The data collected todate suggests that PIK3CA is mutated in approximately 32% of colorectalcancers (Samuels et al., 2004; Ikenoue et al., 2005), 18-40% of breastcancers (Bachman et al., 2004; Campbell et al., 2004; Levine et al.,2005; Seal et al., 2005; Wu et al., 2005), 27% of glioblastomas (Samuelset al., 2004; Hartmann et al., 2005; Gallia et al., 2006), 25% ofgastric cancers (Samuels et al., 2004; Byun et al., 2003; Li et al.,2005), 36% of hepatocellular carcinomas (Lee et al., 2005), 4-12% ofovarian cancers (Levine et al., 2005; Wang et al., 2005), 4% of lungcancers (Samuels et al., 2004; Whyte & Holbeck, 2006), and up to 40% ofendometrial cancers (Oda et al., 2005). PIK3CA mutations have beenreported in oligodendroma, astrocytoma, medulloblastoma, and thyroidtumors as well (Broderick et al., 2004; Garcia-Rostan et al., 2005).Based upon the observed high frequency of mutation. PIK3CA is one of thetwo most frequently mutated genes associated with cancer, the otherbeing K-ras. More than 80% of the PIK3CA mutations cluster within tworegions of the protein, the helical (E545K) and catalytic (H1047R)domains. Biochemical analysis and protein expression studies havedemonstrated that both mutations lead to increased constitutive p110αcatalytic activity and are in fact, oncogenic (Bader et al., 2006; Kanget al., 2005; Samuels et al., 2005; Samuels & Ericson, 2006). Recently,it has been reported that PIK3CA knockout mouse embryo fibroblasts aredeficient in signaling downstream from various growth factor receptors(IGF-1, Insulin, PDGF, EGF), and are resistant to transformation by avariety of oncogenic RTKs (IGFR, wild-type EGFR and somatic activatingmutants of EGFR, Her2/Neu) (Zhao et al., 2006).

Functional studies of PI3K in vivo have demonstrated that siRNA-mediateddownregulation of p110β inhibits both Akt phosphorylation and HeLa celltumor growth in nude mice (Czauderna et al., 2003). In similarexperiments, siRNA-mediated downregulation of p110β was also shown toinhibit the growth of malignant glioma cells in vitro and in vivo (Pu etal., 2006). Inhibition of PI3K function by dominant-negative p85regulatory subunits can block mitogenesis and cell transformation (Huanget al., 1996; Rahimi et al., 1996). Several somatic mutations in thegenes encoding the p85α and p85β regulatory subunits of PI3K that resultin elevated lipid kinase activity have been identified in a number ofcancer cells as well (Janssen et al., 1998; Jimenez et al., 1998; Philpet al., 2001; Jucker et al., 2002; Shekar et al., 2005). NeutralizingPI3K antibodies also block mitogenesis and can induce apoptosis in vitro(Roche et al., 1994; Roche et al., 1998; Bénistant et al., 2000). Invivo proof-of-principle studies using the PI3K inhibitors LY294002 andwortmannin, demonstrate that inhibition of PI3K signaling slows tumorgrowth in vivo (Powis et al., 1994; Schultz et al., 1995; Semba et al.,2002; Ihle et al., 2004).

Overexpression of Class I PI3K activity, or stimulation of their lipidkinase activities, is associated with resistance to both targeted (suchas imatinib and tratsuzumab) and cytotoxic chemotherapeutic approaches,as well as radiation therapy (West et al., 2002; Gupta et al., 2003;Osaki et al., 2004; Nagata et al., 2004; Gottschalk et al., 2005; Kim etal., 2005). Activation of PI3K has also been shown to lead to expressionof multidrug resistant protein-1 (MRP-1) in prostate cancer cells andthe subsequent induction of resistance to chemotherapy (Lee et al.,2004).

The importance of PI3K signaling in tumorigenesis is further underscoredby the findings that the PTEN tumor suppressor, a PI(3)P phosphatase, isamong the most commonly inactivated genes in human cancers (Li et al.,1997; Steck et al., 1997; Ali et al., 1999; Ishii et al., 1999). PTENdephosphorylates PI(3,4,5)P₃ to PI(4,5)P₂ thereby antagonizingPI3K-dependent signaling. Cells containing functionally inactive PTENhave elevated levels of PIP₃, high levels of activity of PI3K signaling(Haas-Kogan et al., 1998; Myers et al., 1998; Taylor et al., 2000),increased proliferative potential, and decreased sensitivity topro-apoptotic stimuli (Stambolic et al., 1998). Reconstitution of afunctional PTEN suppresses PI3K signaling (Taylor et al., 2000),inhibits cell growth and re-sensitizes cells to pro-apoptotic stimuli(Myers et al., 1998; Zhao et al., 2004). Similarly, restoration of PTENfunction in tumors lacking functional PTEN inhibits tumor growth in vivo(Stahl et al., 2003; Su et al., 2003; Tanaka & Grossman, 2003) andsensitizes cells to cytotoxic agents (Tanaka & Grossman, 2003).

The signaling inputs to Class 1 PI3Ks are diverse and can be deducedthrough genetic analyses. Thus, activation of AKT was impaired inp110α-deficient murine embryonic fibroblasts (MEFs) upon stimulation byclassical Receptor Tyrosine Kinase (RTK) ligands (e.g., EGF, insulin,IGF-1, and PDGF) (Zhao et al., 2006). However, MEFs in which p110β isablated or replaced by a kinase-dead allele of p110β respond normally togrowth factor stimulation via RTKs (Jia et al., 2008). In contrast,p110β catalytic activity is required for AKT activation in response toGPCR ligands (such as LPA). As such, p110α appears to carry the majorityof the PI3K signal in classic RTK signaling and is responsible for tumorcell growth, proliferation, survival, angiogenesis and metabolism,whereas p110β mediates GPCR signaling from mitogens and chemokines andtherefore may regulate tumor cell proliferation, metabolism,inflammation and invasion (Vogt et al., 2009; Jia et al., 2009).

The mutation of the gene encoding p110β is rare in tumors, butamplification of PI3Kβ has been found in many tumors (Bénistant et al.,2000; Brugge et al., 2007). Importantly, in a mouse prostate tumor modeldriven by PTEN deficiency, ablation of p110α was shown to have no effecton tumorigenesis (Jia et al., 2008). Furthermore, in PTEN-deficienthuman cancer cell lines (e.g., PC-3, U87MG, and BT549) of p110β, but notp110α, inhibits downstream activation of AKT, cell transformation, andthe growth of PTEN-deficient cells and tumor xenografts (Wee et al.,2008). Genetic studies have suggested that the kinase activity of p110βis essential in cellular transformation caused by PTEN loss. Forexample, adding back a kinase-dead p110β, but not its wild-typecounterpart, impaired focus formation in PTEN-deficient PC3 cellsdepleted for endogenous p110β (Wee et al., 2008). These studiesdemonstrate that PTEN-deficient tumor cells depend on p110β and itscatalytic activity for signaling and growth.

Genetic alteration of tumor suppressor gene PTEN is frequently found inmany cancers (Liu et al., 2009), such as endometrial cancer (43%), CRPC(35-79%), glioma (19%) and melanoma (18%). In the case of endometrialcancer, coexisting PIK3CA and PTEN genetic alteration was confirmed(Yuan & Cantley, 2008). In addition to mutation, amplification of PIK3CAand loss-of-function of PTEN by various molecular mechanisms have beendiscovered. For example, amplification of PIK3CA and loss-of-function ofPTEN was found in 30-50% and 35-60% of gastric cancer patients,respectively, although PIK3CA and PTEN mutation rate was reported to beless than 7% of each (Byun et al., 2003; Oki et al., 2006; Li et al.,2005; Sanger Database).

While a subset of tumor types are solely dependent on PI3Kα signaling,other tumors are dependent on PI3Kβ signaling or on a combination ofboth PI3Kα and PI3Kβ signaling.

Therefore, there remains a need for balanced PI3K α/β inhibitors capableof inhibiting both PI3K alpha and beta targets.

WO 2008/070150 (Bayer Schering Pharma Aktiengesellschaft) relates to2,3-dihydroimidazo[1,2-c]quinazoline compounds, to pharmaceuticalcompositions containing such compounds and the use of such compounds orcompositions for phosphotidylinositol-3-kinase (PI3K) inhibition, andtreating diseases associated with PI3K activity, in particular treatinghyper-proliferative and/or angiogenesis disorders, as a sole agent or incombination with other active ingredients. Said compounds show anincreased activity (lower 1050) against PI3K alpha than against PI3kbeta.

However, the state of the art described above does not describe thecompounds of general formula (I) of the present invention, astereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a saltthereof, or a mixture of same, as described and defined in the claimsherein, and as hereinafter referred to as “compounds of the presentinvention”. Nor does the state of the art described above show thepharmacological activity as shown by the compounds of general formula(I) of the present invention.

It has now been found, and this constitutes the basis of the presentinvention, that said compounds of the present invention, as describedand defined herein, and as hereinafter referred to as “compounds of thepresent invention”, have surprising and advantageous properties: thecompounds of the present invention display surprising balanced activityfor the inhibition of phosphatidylinositol-3-kinase alpha- andbeta-isoforms as shown in the biological section of this text, which isshown as the ratio PI3K beta IC₅₀/PI3K alpha IC₅₀.

The compounds of the present invention, including salts, metabolites,solvates, solvates of salts, hydrates, and stereoisomeric forms thereof,exhibit anti-proliferative activity and are thus useful to prevent ortreat the disorders associated with hyper-proliferation: in particular,said compounds of general formula (I) of the present invention maytherefore be used for the treatment or prophylaxis of diseases ofuncontrolled cell growth, proliferation and/or survival, inappropriatecellular immune responses, or inappropriate cellular inflammatoryresponses or diseases which are accompanied with uncontrolled cellgrowth, proliferation and/or survival, inappropriate cellular immuneresponses, or inappropriate cellular inflammatory responses,particularly in which the uncontrolled cell growth, proliferation and/orsurvival, inappropriate cellular immune responses, or inappropriatecellular inflammatory responses is mediated by the PI3K pathway, suchas, for example, haemotological tumours, solid tumours, and/ormetastases thereof, e.g. leukaemias and myelodysplastic syndrome,malignant lymphomas, head and neck tumours including brain tumours andbrain metastases, tumours of the thorax including non-small cell andsmall cell lung tumours, gastrointestinal tumours, endocrine tumours,mammary and other gynaecological tumours, urological tumours includingrenal, bladder and prostate tumours, skin tumours, and sarcomas, and/ormetastases thereof.

DESCRIPTION OF THE INVENTION

In accordance with a first aspect, the present invention coverscompounds of general formula (I):

is in which:R¹ represents —(CH₂)_(n)—(CHR⁴)—(CH₂)_(m)—N(R⁵)(R^(5′));R² represents a heteroaryl of structure:

-   -   optionally substituted with 1, 2 or 3 R⁶ groups,    -   in which:    -   * represents the point of attachment of said heteroaryl with the        rest of the structure of general formula (I),    -   X represents N or C—R⁶,    -   X′ represents O, S, NH, N—R⁶, N or C—R⁶,    -   with the proviso that when X and X′ are both C—R⁶, then one C—R⁶        is C—H;        R³ is methyl;        R⁴ is hydroxy;        R⁵ is a hydrogen atom, or a C₁-C₆-alkyl,        C₃-C₆-cycloalkyl-C₁-C₆-alkyl, aryl-C₁-C₆-alkyl or        C₁-C₆-alkoxy-C₁-C₆-alkyl,        wherein said aryl-C₁-C₆-alkyl group is substituted, one or more        times, in the same way or differently, with R⁶;        R^(5′) is aryl-C₁-C₆-alkyl,        wherein said aryl-C₁-C₆-alkyl group is substituted, one or more        times, in the same way or differently, with R⁶;        each occurrence of R⁶ may be the same or different and is        independently a hydrogen atom, a halogen atom, C₁-C₆-alkyl,        C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₆-cycloalkyl,        C₃-C₆-cycloalkyl-C₁-C₆-alkyl, aryl, aryl-C₁-C₆-alkyl,        heteroaryl, heteroaryl-C₁-C₆-alkyl, 3- to 8-membered        heterocyclic ring, 3- to 8-membered heterocyclyl-C₁-C₆-alkyl,        —C₁-C₆-alkyl-OR⁷, —C₁-C₆-alkyl-SR⁷, —C₁-C₆-alkyl-N(R⁷)(R^(7′)),        —C₁-C₆-alkyl-C(═O)R⁷, —CN, —C(═O)OR⁷, —C(═O)N(R⁷)(R^(7′)), —OR⁷,        —SR⁷, —N(R⁷)(R^(7′)), or —NR⁷C(═O)R⁷ each of which may be        optionally substituted with 1 or more R⁸ groups;        each occurrence of R⁷ and R^(7′) may be the same or different        and is independently a hydrogen atom, or a C₁-C₆-alkyl,        C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₆-cycloalkyl,        C₃-C₆-cycloalkyl-C₁-C₆-alkyl, C₃-C₆-cycloalkenyl, aryl,        aryl-C₁-C₆-alkyl, heteroaryl, 3- to 8-membered heterocyclic        ring, 3- to 8-membered heterocyclyl-C₁-C₆-alkyl, or        heteroaryl-C₁-C₆-alkyl;        each occurrence of R⁸ is independently a halogen atom, or nitro,        hydroxy, cyano, formyl, acetyl, amino, C₁-C₆-alkyl,        C₁-C₆-alkoxy, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₆-cycloalkyl,        C₃-C₆-cycloalkyl-C₁-C₆-alkyl, C₁-C₆-cycloalkenyl, aryl,        aryl-C₁-C₆-alkyl, heteroaryl, 3- to 8-membered heterocyclic        ring, heterocyclyl-C₁-C₆-alkyl, or heteroaryl-C₁-C₆-alkyl;        n is an integer of 1 and m is an integer of 1;        or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate,        or a salt thereof, in particular a physiologically acceptable        salt, or a mixture of same.

DEFINITIONS

The terms as mentioned in the present text have preferably the followingmeanings:

The term “halogen atom” or “halo” is to be understood as meaning afluorine, chlorine, bromine or iodine atom.

The term “C₁-C₆-alkyl” is to be understood as preferably meaning alinear or branched, saturated, monovalent hydrocarbon group having 1, 2,3, 4, 5 or 6 carbon atoms, e.g. a methyl, ethyl, propyl, butyl, pentyl,hexyl, iso-propyl, iso-butyl, sec-butyl, tert-butyl, iso-pentyl,2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl,neo-pentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl,2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl,3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl,2,3-dimethylbutyl, 1,3-dimethylbutyl, or 1,2-dimethylbutyl group, or anisomer thereof. Particularly, said group has 1, 2 or 3 carbon atoms(“C₁-C₃-alkyl”), methyl, ethyl, n-propyl- or iso-propyl.

The term “halo-C₁-C₆-alkyl” is to be understood as preferably meaning alinear or branched, saturated, monovalent hydrocarbon group in which theterm “C₁-C₆-alkyl” is defined supra, and in which one or more hydrogenatoms is replaced by a halogen atom, in identically or differently, i.e.one halogen atom being independent from another. Particularly, saidhalogen atom is F. Said halo-C₁-C₆-alkyl group is, for example, —CF₃,—CHF₂, —CH₂F, —CF₂CF₃, or —CH₂CF₃.

The term “C₁-C₆-alkoxy” is to be understood as preferably meaning alinear or branched, saturated, monovalent, hydrocarbon group of formula—O-alkyl, in which the term “alkyl” is defined supra, e.g. a methoxy,ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, tert-butoxy,sec-butoxy, pentoxy, iso-pentoxy, or n-hexoxy group, or an isomerthereof.

The term “halo-C₁-C₆-alkoxy” is to be understood as preferably meaning alinear or branched, saturated, monovalent C₁-C₆-alkoxy group, as definedsupra, in which one or more of the hydrogen atoms is replaced, inidentically or differently, by a halogen atom. Particularly, saidhalogen atom is F. Said halo-C₁-C₆-alkoxy group is, for example, —OCF₃,—OCHF₂, —OCH₂F, —OCF₂CF₃, or —OCH₂CF₃.

The term “C₁-C₆-alkoxy-C₁-C₆-alkyl” is to be understood as preferablymeaning a linear or branched, saturated, monovalent alkyl group, asdefined supra, in which one or more of the hydrogen atoms is replaced,in identically or differently, by a C₁-C₆-alkoxy group, as definedsupra, e.g. methoxyalkyl, ethoxyalkyl, propyloxyalkyl, iso-propoxyalkyl,butoxyalkyl, iso-butoxyalkyl, tert-butoxyalkyl, sec-butoxyalkyl,pentyloxyalkyl, iso-pentyloxyalkyl, hexyloxyalkyl group, in which theterm “C₁-C₆-alkyl” is defined supra, or an isomer thereof.

The term “halo-C₁-C₆-alkoxy-C₁-C₆-alkyl” is to be understood aspreferably meaning a linear or branched, saturated, monovalentC₁-C₆-alkoxy-C₁-C₆-alkyl group, as defined supra, in which one or moreof the hydrogen atoms is replaced, in identically or differently, by ahalogen atom. Particularly, said halogen atom is F. Saidhalo-C₁-C₆-alkoxy-C₁-C₆-alkyl group is, for example, —CH₂CH₂OCF₃,—CH₂CH₂OCHF₂, —CH₂CH₂OCH₂F, —CH₂CH₂OCF₂CF₃, or —CH₂CH₂OCH₂CF₃.

The term “C₂-C₆-alkenyl” is to be understood as preferably meaning alinear or branched, monovalent hydrocarbon group, which contains one ormore double bonds, and which has 2, 3, 4, 5, or 6 carbon atoms,particularly 2 or 3 carbon atoms (“C₂-C₃-alkenyl”), it being understoodthat in the case in which said alkenyl group contains more than onedouble bond, then said double bonds may be isolated from, or conjugatedwith, each other. Said alkenyl group is, for example, a vinyl, allyl,(E)-2-methylvinyl, (Z)-2-methylvinyl, homoallyl, (E)-but-2-enyl,(Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, pent-4-enyt,(E)-pent-3-enyl, (Z)-pent-3-enyl, (E)-pent-2-enyl, (Z)-pent-2-enyl,(E)-pent-1-enyl, (Z)-pent-1-enyl, hex-5-enyl, (E)-hex-4-enyl,(Z)-hex-4-enyl, (E)-hex-3-enyl, (Z)-hex-3-enyl, (E)-hex-2-enyl,(Z)-hex-2-enyl, (E)-hex-1-enyl, (Z)-hex-1-enyl, isopropenyl,2-methylprop-2-enyl, 1-methylprop-2-enyl, 2-methylprop-1-enyl,(E)-1-methylprop-1-enyl, (Z)-1-methylprop-1-enyl, 3-methylbut-3-enyl,2-methylbut-3-enyl, 1-methylbut-3-enyl, 3-methylbut-2-enyl,(E)-2-methylbut-2-enyl, (Z)-2-methylbut-2-enyl, (E)-1-methylbut-2-enyl,(Z)-1-methylbut-2-enyl, (E)-3-methylbut-1-enyl, (Z)-3-methylbut-1-enyl,(E)-2-methylbut-1-enyl, (Z)-2-methylbut-1-enyl, (E)-1-methylbut-1-enyl,(Z)-1-methylbut-1-enyl, 1,1-dimethylprop-2-enyl, 1-ethylprop-1-enyl,1-propylvinyl, 1-isopropylvinyl, 4-methylpent-4-enyl,3-methylpent-4-enyl, 2-methylpent-4-enyl, 1-methylpent-4-enyl,4-methylpent-3-enyl, (E)-3-methylpent-3-enyl, (Z)-3-methylpent-3-enyl,(E)-2-methylpent-3-enyl, (Z)-2-methylpent-3-enyl,(E)-1-methylpent-3-enyl, (Z)-1-methylpent-3-enyl,(E)-4-methylpent-2-enyl, (Z)-4-methylpent-2-enyl,(E)-3-methylpent-2-enyl, (Z)-3-methylpent-2-enyl,(E)-2-methylpent-2-enyl, (Z)-2-methylpent-2-enyl,(E)-1-methylpent-2-enyl, (Z)-1-methylpent-2-enyl,(E)-4-methylpent-1-enyl, (Z)-4-methylpent-1-enyl,(E)-3-methylpent-1-enyl, (Z)-3-methylpent-1-enyl,(E)-2-methylpent-1-enyl, (Z)-2-methylpent-1-enyl,(E)-1-methylpent-1-enyl, (Z)-1-methylpent-1-enyl, 3-ethylbut-3-enyl,2-ethylbut-3-enyl, 1-ethylbut-3-enyl, (E)-3-ethylbut-2-enyl,(Z)-3-ethylbut-2-enyl, (E)-2-ethylbut-2-enyl, (Z)-2-ethylbut-2-enyl,(E)-1-ethylbut-2-enyl, (Z)-1-ethylbut-2-enyl, (E)-3-ethylbut-1-enyl,(Z)-3-ethylbut-1-enyl, 2-ethylbut-1-enyl, (E)-1-ethylbut-1-enyl,(Z)-1-ethylbut-1-enyl, 2-propylprop-2-enyl, 1-propylprop-2-enyl,2-isopropylprop-2-enyl, 1-isopropylprop-2-enyl, (E)-2-spropylprop-1-enyl, (Z)-2-propylprop-1-enyl, (E)-1-propylprop-1-enyl,(Z)-1-propylprop-1-enyl, (E)-2-isopropylprop-1-enyl,(Z)-2-isopropylprop-1-enyl, (E)-1-isopropylprop-1-enyl,(Z)-1-isopropylprop-1-enyl, (E)-3,3-dimethylprop-1-enyl,(Z)-3,3-dimethylprop-1-enyl, 1-(1,1-dimethylethyl)ethenyl,buta-1,3-dienyl, penta-1,4-dienyl, hexa-1,5-dienyl, or methylhexadienylgroup. Particularly, said group is vinyl or allyl.

The term “C₂-C₆-alkynyl” is to be understood as preferably meaning alinear or branched, monovalent hydrocarbon group which contains one ormore triple bonds, and which contains 2, 3, 4, 5, or 6 carbon atoms,particularly 2 or 3 carbon atoms (“C₂-C₃-alkynyl”). Said C₂-C₆-alkynylgroup is, for example, ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl,but-2-ynyl, but-3-ynyl, pent-1-ynyl, pent-2-ynyl, pent-3-ynyl,pent-4-ynyl, hex-1-ynyl, hex-2-inyl, hex-3-inyl, hex-4-ynyl, hex-5-ynyl,1-methylprop-2-ynyl, 2-methylbut-3-ynyl, 1-methylbut-3-ynyl,1-methylbut-2-ynyl, 3-methylbut-1-ynyl, 1-ethylprop-2-ynyl,3-methylpent-4-ynyl, 2-methylpent-4-ynyl, 1-methylpent-4-ynyl,2-methylpent-3-ynyl, 1-methylpent-3-ynyl, 4-methylpent-2-ynyl,1-methylpent-2-ynyl, 4-methylpent-1-ynyl, 3-methylpent-1-ynyl,2-ethylbut-3-ynyl, 1-ethylbut-3-ynyl, 1-ethylbut-2-ynyl,1-propylprop-2-ynyl, 1-isopropylprop-2-ynyl, 2,2-dimethylbut-3-inyl,1,1-dimethylbut-3-ynyl, 1,1-dimethylbut-2-ynyl, or3,3-dimethylbut-1-ynyl group. Particularly, said alkynyl group isethynyl, prop-1-ynyl, or prop-2-inyl.

The term “C₃-C₆-cycloalkyl” is to be understood as preferably meaning asaturated, monovalent, mono-, or bicyclic hydrocarbon ring whichcontains 3, 4, 5, or 6 carbon atoms. Said C₃-C₆-cycloalkyl group is forexample, a monocyclic hydrocarbon ring, e.g. a cyclopropyl, cyclobutyl,cyclopentyl, or cyclohexyl group, or a bicyclic hydrocarbon ring, e.g. aperhydropentalenylene or decalin ring. Said cycloalkyl ring canoptionally contain one or more double bonds e.g. cycloalkenyl, such as acyclopropenyl, cyclobutenyl, cyclopentenyl or cyclohexenyl group,wherein the bond between said ring with the rest of the molecule may beto any carbon atom of said ring, be it saturated or unsaturated.

The term “alkylene” is understood as preferably meaning an optionallysubstituted hydrocarbon chain (or “tether”) having 1, 2, 3, 4, 5, or 6carbon atoms, i.e. an optionally substituted —CH₂— (“methylene” or“single membered tether” or, for example —C(Me)₂-), —CH₂—CH₂—(“ethylene”, “dimethylene”, or “two-membered tether”), —CH₂—CH₂—CH₂—(“propylene”, “trimethylene”, or “three-membered tether”), to—CH₂—CH₂—CH₂—CH₂— (“butylene”, “tetramethylene”, or “four-memberedtether”), —CH₂—CH₂—CH₂—CH₂—CH₂— (“pentylene”, “pentamethylene” or“five-membered ether”), or —CH₂—CH₂—CH₂—CH₂—CH₂—CH₂— (“hexylene”,“hexamethylene”, or six-membered tether”) group. Particularly, saidalkylene tether has 1, 2, 3, 4, or 5 carbon atoms, more particularly 1or 2 carbon atoms.

The term “3- to 8-membered heterocycloalkyl”, is to be understood asmeaning a saturated, monovalent, mono- or bicyclic hydrocarbon ringwhich contains 2, 3, 4, 5, 6 or 7 carbon atoms, and one or moreheteroatom-containing groups selected from C(═O), O, S, S(═O), S(═O)₂,NR^(a), in which R^(a) represents a hydrogen atom, or a C₁-C₆-alkyl- orhalo-C₁-C₆-alkyl- group; it being possible for said heterocycloalkylgroup to be attached to the rest of the molecule via any one of thecarbon atoms or, if present, the nitrogen atom.

Particularly, said 3- to 8-membered heterocycloalkyl can contain 2, 3,4, 5, 6 or 7 carbon atoms, and one or more of the above-mentionedheteroatom-containing groups (a “3- to 8-membered heterocycloalkyl”),more particularly said heterocycloalkyl can contain 4 or 5 carbon atoms,and one or more of the above-mentioned heteroatom-containing groups (a“5- to 7-membered heterocycloalkyl”).

Particularly, without being limited thereto, said heterocycloalkyl canbe a 4-membered ring, such as an azetidinyl, oxetanyl, or a 5-memberedring, such as tetrahydrofuranyl, dioxolinyl, pyrrolidinyl,imidazolidinyl, pyrazolidinyl, pyrrolinyl, or a 6-membered ring, such astetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl,piperazinyl, or trithianyl, or a 7-membered ring, such as a diazepanylring, for example. Optionally, said heterocycloalkyl can be benzo fused.

Said heterocyclyl can be bicyclic, such as, without being limitedthereto, a 5,5-membered ring, e.g. ahexahydrocyclopenta[c]pyrrol-2(1H)-yl) ring, or a 5,6-membered bicyclicring, e.g. a hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl ring, or8-oxa-3-azabicyclo[3.2.1]oct-3-yl ring, for example.

As mentioned supra, said nitrogen atom-containing ring can be partiallyunsaturated, i.e. it can contain one or more double bonds, such as,without being limited thereto, a 2,5-dihydro-1H-pyrrolyl,4H-[1,3,4]thiadiazinyl, 4,5-dihydrooxazolyl, or 4H-[1,4]thiazinyl ring,for example, or, it may be benzo-fused, such as, without being limitedthereto, a dihydroisoquinolinyl ring, for example.

The term “aryl” is to be understood as preferably meaning a monovalent,aromatic or partially aromatic, mono-, or bi- or tricyclic hydrocarbonring having 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms (a“C₆-C₁₄-aryl” group), particularly a ring having 6 carbon atoms (a“C₆-aryl” group), e.g. a phenyl group; or a biphenyl group, or a ringhaving 9 carbon atoms (a “C₉-aryl” group), e.g. an indanyl or indenylgroup, or a ring having 10 carbon atoms (a “C₁₀-aryl” group), e.g. atetralinyl, dihydronaphthyl, or naphthyl group, or a ring having 13carbon atoms, (a “C₁₃-aryl” group), e.g. a fluorenyl group, or a ringhaving 14 carbon atoms, (a “C₁₄-aryl” group), e.g. an anthranyl group. Aparticular example of an aryl group is one of the following possiblestructures:

in which z represents O, S, NH or N(C₁-C₆-alkyl), and * indicates thepoint of attachment of said aryl group with the rest of the molecule.

The term “heteroaryl” is understood as preferably meaning a monovalent,monocyclic-, bicyclic- or tricyclic aromatic ring system having 5, 6, 7,8, 9, 10, 11, 12, 13 or 14 ring atoms (a “5- to 14-membered heteroaryl”group), particularly 5 or 6 or 9 or 10 atoms, and which contains atleast one heteroatom which may be identical or different, saidheteroatom being such as oxygen, nitrogen or sulfur, and in addition ineach case can be benzocondensed.

Particularly, said heteroaryl is of structure:

-   -   optionally substituted with 1, 2 or 3 R⁶ groups,    -   in which:    -   * represents the point of attachment of said heteroaryl with the        rest of the compound of general formula (I) as defined supra,    -   X represents N or C—R⁶,    -   X′ represents O, S, NH, N—R⁶, N or C—R⁶,        -   each occurrence of R⁶ may be the same or different and is            independently a hydrogen atom, a halogen atom, C₁-C₆-alkyl,            C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₆-cycloalkyl,            C₃-C₆-cycloalkyl-C₁-C₆-alkyl, aryl, aryl-C₁-C₆-alkyl,            heteroaryl, heteroaryl-C₁-C₆-alkyl, 3- to 8-membered            heterocyclic ring, 3- to 8-membered            heterocyclyl-C₁-C₆-alkyl, —C₁-C₆-alkyl-OR⁷,            —C₁-C₆-alkyl-SR⁷, —C₁-C₆-alkyl-N(R⁷)(R^(7′)),            —C₁-C₆-alkyl-C(═O)R⁷, —CN, —C(═O)OR⁷, —C(═O)N(R⁷)(R^(7′)),            —OR⁷, —SR⁷, —N(R⁷)(R^(7′)), or —NR⁷C(═O)R⁷ each of which may            be optionally substituted with 1 or more R⁸ groups;    -   each occurrence of R⁷ and R^(7′) may be the same or different        and is independently a hydrogen atom, or a C₁-C₆-alkyl,        C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₆-cycloalkyl,        C₃-C₆-cycloalkyl-C₁-C₆-alkyl, C₃-C₆-cycloalkenyl, aryl,        aryl-C₁-C₆-alkyl, heteroaryl, 3- to 8-membered heterocyclic        ring, 3- to 8-membered heterocyclyl-C₁-C₆-alkyl, or        heteroaryl-C₁-C₆-alkyl;    -   each occurrence of R⁸ is independently a halogen atom, or nitro,        hydroxy, cyano, formyl, acetyl, amino, C₁-C₆-alkyl,        C₁-C₆-alkoxy, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₆-cycloalkyl,        C₃-C₆-cycloalkyl-C₁-C₆-alkyl, C₁-C₆-cycloalkenyl, aryl,        aryl-C₁-C₆-alkyl, heteroaryl, 3- to 8-membered heterocyclic        ring, heterocyclyl-C₁-C₆-alkyl, or heteroaryl-C₁-C₆-alkyl.

More particularly, said heteroaryl is selected from thienyl, furanyl,pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl,isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyletc., and benzo derivatives thereof, such as, for example, benzofuranyl,benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl,benzotriazolyl, indazolyl, indolyl, isoindolyl, etc.; or pyridyl,pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and benzoderivatives thereof, such as, for example, quinolinyl, quinazolinyl,isoquinolinyl, etc.; or azocinyl, indolizinyl, purinyl, etc., and benzoderivatives thereof; or cinnolinyl, phthalazinyl, quinazolinyl,quinoxalinyl, naphthpyridinyl, pteridinyl, carbazolyl, acridinyl,phenazinyl, phenothiazinyl, phenoxazinyl, xanthenyl, or oxepinyl, etc.

In general, and unless otherwise mentioned, the heteroarylic orheteroarylenic radicals include all the possible isomeric forms thereof,e.g. the positional isomers thereof. Thus, for some illustrativenon-restricting example, the term pyridinyl or pyridinylene includespyridin-2-yl, pyridin-2-ylene, pyridin-3-yl, pyridin-3-ylene,pyridin-4-yl and pyridin-4-ylene; or the term thienyl or thienyleneincludes thien-2-yl, thien-2-ylene, thien-3-yl and thien-3-ylene.

The term “C₁-C₆”, as used throughout this text, e.g. in the context ofthe definition of “C₁-C₆-alkyl”, “C₁-C₆-haloalkyl”, “C₁-C₆-alkoxy”, or“C₁-C₆-haloalkoxy” is to be understood as meaning an alkyl group havinga finite number of carbon atoms of 1 to 6, i.e. 1, 2, 3, 4, 5, or 6carbon atoms. It is to be understood further that said term “C₁-C₆” isto be interpreted as any sub-range comprised therein, e.g. C₁-C₆, C₂-C₅,C₃-C₄, C₁-C₂, C₁-C₃, C₁-C₄, C₁-C₅, C₁-C₆; particularly C₁-C₂, C₁-C₃,C₁-C₄, C₁-C₅, C₁-C₆; more particularly C₁-C₄; in the case of“C₁-C₆-haloalkyl” or “C₁-C₆-haloalkoxy” even more particularly C₁-C₂.

Similarly, as used herein, the term “C₂-C₈”, as used throughout thistext, e.g. in the context of the definitions of “C₂-C₆-alkenyl” and“C₂-C₆-alkynyl”, is to be understood as meaning an alkenyl group or analkynyl group having a finite number of carbon atoms of 2 to 6, i.e. 2,3, 4, 5, or 6 carbon atoms. It is to be understood further that saidterm “C₂-C₆” is to be interpreted as any sub-range comprised therein,e.g. C₂-C₆, C₃-C₅, C₃-C₄, C₂-C₃, C₂-C₄, C₂-C₅; particularly C₂-C₃.

Further, as used herein, the term “C₃-C₆”, as used throughout this text,e.g. in the context of the definition of “C₃-C₆-cycloalkyl”, is to beunderstood as meaning a cycloalkyl group having a finite number ofcarbon atoms of 3 to 6, i.e. 3, 4, 5 or 6 carbon atoms. It is to beunderstood further that said term “C₃-C₆” is to be interpreted as anysub-range comprised therein, e.g. C₃-C₆, C₄-C₅, C₃-C₅, C₃-C₄, C₄-C₆,C₅-C₆; particularly C₃-C₆.

The term “substituted” means that one or more hydrogens on thedesignated atom is replaced with a selection from the indicated group,provided that the designated atom's normal valency under the existingcircumstances is not exceeded, and that the substitution results in astable compound. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds.

The term “optionally substituted” means optional substitution with thespecified groups, radicals or moieties.

Ring system substituent means a substituent attached to an aromatic ornonaromatic ring system which, for example, replaces an availablehydrogen on the ring system.

As used herein, the term “one or more times”, e.g. in the definition ofthe substituents of the compounds of the general formulae of the presentinvention, is understood as meaning “one, two, three, four or fivetimes, particularly one, two, three or four times, more particularlyone, two or three times, even more particularly one or two times”.

Where the plural form of the word compounds, salts, polymorphs,hydrates, solvates and the like, is used herein, this is taken to meanalso a single compound, salt, polymorph, isomer, hydrate, solvate or thelike.

By “stable compound’ or “stable structure” is meant a compound that issufficiently robust to survive isolation to a useful degree of purityfrom a reaction mixture, and formulation into an efficacious therapeuticagent.

The compounds of this invention may contain one or more asymmetriccentre, depending upon the location and nature of the varioussubstituents desired. Asymmetric carbon atoms may be present in the (R)or (S) configuration, resulting in racemic mixtures in the case of asingle asymmetric centre, and diastereomeric mixtures in the case ofmultiple asymmetric centres. In certain instances, asymmetry may also bepresent due to restricted rotation about a given bond, for example, thecentral bond adjoining two substituted aromatic rings of the specifiedcompounds.

Substituents on a ring may also be present in either cis or trans form.It is intended that all such configurations (including enantiomers anddiastereomers), are included within the scope of the present invention.

Preferred compounds are those which produce the more desirablebiological activity. Separated, pure or partially purified isomers andstereoisomers or racemic or diastereomeric mixtures of the compounds ofthis invention are also included within the scope of the presentinvention. The purification and the separation of such materials can beaccomplished by standard techniques known in the art.

The optical isomers can be obtained by resolution of the racemicmixtures according to conventional processes, for example, by theformation of diastereoisomeric salts using an optically active acid orbase or formation of covalent diastereomers. Examples of appropriateacids are tartaric, diacetyltartaric, ditoluoyltartaric andcamphorsulfonic acid. Mixtures of diastereoisomers can be separated intotheir individual diastereomers on the basis of their physical and/orchemical differences by methods known in the art, for example, bychromatography or fractional crystallisation. The optically active basesor acids are then liberated from the separated diastereomeric salts. Adifferent process for separation of optical isomers involves the use ofchiral chromatography (e.g., chiral HPLC columns), with or withoutconventional derivatisation, optimally chosen to maximise the separationof the enantiomers. Suitable chiral HPLC columns are manufactured byDiacel, e.g., Chiracel OD and Chiracel OJ among many others, allroutinely selectable. Enzymatic separations, with or withoutderivatisation, are also useful. The optically active compounds of thisinvention can likewise be obtained by chiral syntheses utilizingoptically active starting materials.

In order to limit different types of isomers from each other referenceis made to IUPAC Rules Section E (Pure Appl Chem 45, 11-30, 1976).

The present invention includes all possible stereoisomers of thecompounds of the present invention as single stereoisomers, or as anymixture of said stereoisomers, in any ratio. Isolation of a singlestereoisomer, e.g. a single enantiomer or a single diastereomer, of acompound of the present invention may be achieved by any suitable stateof the art method, such as chromatography, especially chiralchromatography, for example.

Tautomers, sometimes referred to as proton-shift tautomers, are two ormore compounds that are related by the migration of a hydrogen atomaccompanied by the switch of one or more single bonds and one or moreadjacent double bonds. The compounds of this invention may exist in oneor more tautomeric forms. For example, a compound of Formula I may existin tautomeric form Ia, tautomeric form Ib, or tautomeric form Ic, or mayexist as a mixture of any of these forms. It is intended that all suchtautomeric forms are included within the scope of the present invention.

Furthermore, any compound of the present invention which contains apyrazole moiety as a heteroaryl group for example can exist as a 1Htautomer, or a 2H tautomer, or even a mixture in any amount of the twotautomers, or a triazole moiety for example can exist as a 1H tautomer,a 2H tautomer, or a 4H tautomer, or even a mixture in any amount of said1H, 2H and 4H tautomers, viz.:

The present invention includes all possible tautomers of the compoundsof the present invention as single tautomers, or as any mixture of saidtautomers, in any ratio.

Further, the compounds of the present invention can exist as N-oxides,which are defined in that at least one nitrogen of the compounds of thepresent invention is oxidised. The present invention includes all suchpossible N-oxides.

The present invention also relates to useful forms of the compounds asdisclosed herein, such as metabolites, hydrates, solvates, prodrugs,salts, in particular pharmaceutically acceptable salts, andco-precipitates.

The compounds of the present invention can exist as a hydrate, or as asolvate, wherein the compounds of the present invention contain polarsolvents, in particular water, methanol or ethanol for example asstructural element of the crystal Lattice of the compounds. The amountof polar solvents, in particular water, may exist in a stoichiometric ornon-stoichiometric ratio. In the case of stoichiometric solvates, e.g. ahydrate, hemi-, (semi-), mono-, sesqui-, di-, tri-, tetra-, penta- etc.solvates or hydrates, respectively, are possible. The present inventionincludes all such hydrates or solvates.

Further, the compounds of the present invention can exist in free form,e.g. as a free base, or as a free acid, or as a zwitterion, or can existin the form of a salt. Said salt may be any salt, either an organic orinorganic addition salt, particularly any pharmaceutically acceptableorganic or inorganic addition salt, customarily used in pharmacy.

The term “pharmaceutically acceptable salt” refers to a relativelynon-toxic, inorganic or organic acid addition salt of a compound of thepresent invention. For example, see S. M. Berge, et al. “PharmaceuticalSalts,” J. Pharm. Sci. 1977, 66, 1-19.

A suitable pharmaceutically acceptable salt of the compounds of thepresent invention may be, for example, an acid-addition salt of acompound of the present invention bearing a nitrogen atom, in a chain orin a ring, for example, which is sufficiently basic, such as anacid-addition salt with an inorganic acid, such as hydrochloric,hydrobromic, hydroiodic, sulfuric, bisulfuric, phosphoric, or nitricacid, for example, or with an organic acid, such as formic, acetic,acetoacetic, pyruvic, trifluoroacetic, propionic, butyric, hexanoic,heptanoic, undecanoic, lauric, benzoic, salicylic,2-(4-hydroxybenzoyl)-benzoic, camphoric, cinnamic,cyclopentanepropionic, digluconic, 3-hydroxy-2-naphthoic, nicotinic,pamoic, pectinic, persulfuric, 3-phenylpropionic, picric, pivalic,2-hydroxyethanesulfonate, itaconic, sulfamic, trifluoromethanesulfonic,dodecylsulfuric, ethansulfonic, benzenesulfonic, para-toluenesulfonic,methansulfonic, 2-naphthalenesulfonic, naphthalinedisulfonic,camphorsulfonic acid, citric, tartaric, stearic, lactic, oxalic,malonic, succinic, malic, adipic, alginic, maleic, fumaric, D-gluconic,mandelic, ascorbic, glucoheptanoic, glycerophosphoric, aspartic,sulfosalicylic, hemisulfuric, or thiocyanic acid, for example.

Further, another suitably pharmaceutically acceptable salt of a compoundof the present invention which is sufficiently acidic, is an alkalimetal salt, for example a sodium or potassium salt, an alkaline earthmetal salt, for example a calcium or magnesium salt, an ammonium salt ora salt with an organic base which affords a physiologically acceptablecation, for example a salt with N-methyl-glucamine, dimethyl-glucamine,ethyl-glucamine, lysine, dicyclohexylamine, 1,6-hexadiamine,ethanolamine, glucosamine, sarcosine, serinol,tris-hydroxy-methyl-aminomethane, aminopropandiol, sovak-base,1-amino-2,3,4-butantriol. Additionally, basic nitrogen containing groupsmay be quaternised with such agents as lower alkyl halides such asmethyl, ethyl, propyl, and butyl chlorides, bromides and iodides;dialkyl sulfates like dimethyl, diethyl, and dibutyl sulfate; and diamylsulfates, long chain halides such as decyl, lauryl, myristyl andstrearyl chlorides, bromides and iodides, aralkyl halides like benzyland phenethyl bromides and others.

Those skilled in the art will further recognise that acid addition saltsof the claimed compounds may be prepared by reaction of the compoundswith the appropriate inorganic or organic acid via any of a number ofknown methods. Alternatively, alkali and alkaline earth metal salts ofacidic compounds of the invention are prepared by reacting the compoundsof the invention with the appropriate base via a variety of knownmethods.

The present invention includes all possible salts of the compounds ofthe present invention as single salts, or as any mixture of said salts,in any ratio.

As used herein, the term “in vivo hydrolysable ester” is understood asmeaning an in vivo hydrolysable ester of a compound of the presentinvention containing a carboxy or hydroxy group, for example, apharmaceutically acceptable ester which is hydrolysed in the human oranimal body to produce the parent acid or alcohol. Suitablepharmaceutically acceptable esters for carboxy include for examplealkyl, cycloalkyl and optionally substituted phenylalkyl, in particularbenzyl esters, C₁-C₆ alkoxymethyl esters, e.g. methoxymethyl, C₁-C₆alkanoyloxymethyl esters, e.g. pivaloyloxymethyl, phthalidyl esters,C₃-C₈ cycloalkoxy-carbonyloxy-C₁-C₆ alkyl esters, e.g.1-cyclohexylcarbonyloxyethyl; 1,3-dioxolen-2-onylmethyl esters, e.g.5-methyl-1,3-dioxolen-2-onylmethyl; and C₁-C₆-alkoxycarbonyloxyethylesters, e.g. 1-methoxycarbonyloxyethyl, and may be formed at any carboxygroup in the compounds of this invention.

An in vivo hydrolysable ester of a compound of the present inventioncontaining a hydroxy group includes inorganic esters such as phosphateesters and [alpha]-acyloxyalkyl ethers and related compounds which as aresult of the in vivo hydrolysis of the ester breakdown to give theparent hydroxy group. Examples of [alpha]-acyloxyalkyl ethers includeacetoxymethoxy and 2,2-dimethylpropionyloxymethoxy. A selection of invivo hydrolysable ester forming groups for hydroxy include alkanoyl,benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl,alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl andN-(dialkylaminoethyl)-N-alkylcarbamoyl (to give carbamates),dialkylaminoacetyl and carboxyacetyl. The present invention covers allsuch esters.

Furthermore, the present invention includes all possible crystallineforms, or polymorphs, of the compounds of the present invention, eitheras single polymorphs, or as a mixture of more than one polymorphs, inany ratio.

In accordance with a second aspect, the present invention coverscompounds of general formula (I), supra, in which:

R¹ represents —(CH₂)_(n)—(CHR⁴)—(CH₂)_(m)—N(R⁵)(R⁵)R² represents a heteroaryl of structure:

in which:

-   -   * represents the point of attachment of said heteroaryl with the        rest of the structure of general formula (I);        R³ is methyl;        R⁴ is hydroxy;        R⁵ is a hydrogen atom, or a C₁-C₆-alkyl,        C₃-C₆-cycloalkyl-C₁-C₆-alkyl, aryl-C₁-C₆-alkyl or        C₁-C₆-alkoxy-C₁-C₆-alkyl,        wherein said aryl-C₁-C₆-alkyl group is substituted, one or more        times, in the same way or differently, with R⁶;        R^(5′) is aryl-C₁-C₆-alkyl,        wherein said aryl-C₁-C₆-alkyl group is substituted, one or more        times, in the same way or differently, with R⁶;        each occurrence of R⁶ may be the same or different and is        independently a hydrogen atom, a methyl group;        each occurrence of R⁷ and R^(7′) may be the same or different        and is independently a hydrogen atom, or a C₁-C₆-alkyl,        C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₆-cycloalkyl,        C₃-C₆-cycloalkyl-C₁-C₆-alkyl, C₃-C₆-cycloalkenyl, aryl,        aryl-C₁-C₆-alkyl, heteroaryl, 3- to 8-membered heterocyclic        ring, 3- to 8-membered heterocyclyl-C₁-C₆-alkyl, or        heteroaryl-C₁-C₆-alkyl;        each occurrence of R⁸ is independently a halogen atom, or nitro,        hydroxy, cyano, formyl, acetyl, amino, C₁-C₆-alkyl,        C₁-C₆-alkoxy, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₆-cycloalkyl,        C₃-C₆-cycloalkyl-C₁-C₆-alkyl, C₁-C₆-cycloalkenyl, aryl,        aryl-C₁-C₆-alkyl, heteroaryl, 3- to 8-membered heterocyclic        ring, heterocyclyl-C₁-C₆-alkyl, or heteroaryl-C₁-C₆-alkyl;        n is an integer of 1 and m is an integer of 1;        or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate,        or a salt thereof, in particular a physiologically acceptable        salt, or a mixture of same.

In accordance with a third aspect, the present invention coverscompounds of general formula (I), supra, in which:

R¹ represents —(CH₂)_(n)—(CHR⁴)—(CH₂)_(m)—N(R⁵)(R^(5′));R² represents a heteroaryl of structure:

in which:

-   -   * represents the point of attachment of said heteroaryl with the        rest of the structure of general formula (I);        R³ is methyl;        R⁴ is hydroxy;        R⁵ is a hydrogen atom, or a C₁-C₆-alkyl,        C₃-C₆-cycloalkyl-C₁-C₆-alkyl, aryl-C₁-C₆-alkyl or        C₁-C₆-alkoxy-C₁-C₆-alkyl,        wherein said aryl-C₁-C₆-alkyl group is substituted, one or more        times, in the same way or differently, with R⁶;        R^(5′) is aryl-C₁-C₆-alkyl,        wherein said aryl-C₁-C₆-alkyl group is substituted, one or more        times, in the same way or differently, with R⁶;        each occurrence of R⁶ may be the same or different and is        independently a hydrogen atom, a methyl group;        each occurrence of R⁷ and R^(7′) may be the same or different        and is independently a hydrogen atom, or a C₁-C₆-alkyl,        C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₆-cycloalkyl,        C₃-C₆-cycloalkyl-C₁-C₆-alkyl, C₃-C₆-cycloalkenyl, aryl,        aryl-C₁-C₆-alkyl, heteroaryl, 3- to 8-membered heterocyclic        ring, 3- to 8-membered heterocyclyl-C₁-C₆-alkyl, or        heteroaryl-C₁-C₆-alkyl;        each occurrence of R⁸ is independently a halogen atom, or nitro,        hydroxy, cyano, formyl, acetyl, amino, C₁-C₆-alkyl,        C₁-C₆-alkoxy, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₆-cycloalkyl,        C₃-C₆-cycloalkyl-C₁-C₆-alkyl, C₁-C₆-cycloalkenyl, aryl,        aryl-C₁-C₆-alkyl, heteroaryl, 3- to 8-membered heterocyclic        ring, heterocyclyl-C₁-C₆-alkyl, or heteroaryl-C₁-C₆-alkyl;        n is an integer of 1 and m is an integer of 1;        or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate,        or a salt thereof, in particular a physiologically acceptable        salt, or a mixture of same.

In accordance with a fourth aspect, the present invention coverscompounds of general formula (I), supra, in which:

R¹ represents —(CH₂)_(n)—(CHR⁴)—(CH₂)_(m)—N(R⁵)(R⁵);R² represents a heteroaryl of structure:

in which:

-   -   * represents the point of attachment of said heteroaryl with the        rest of the structure of general formula (I), and    -   Z represents N or C—R⁶;        R³ is methyl;        R⁴ is hydroxy;        R⁵ is a hydrogen atom, or a C₁-C₆-alkyl,        C₃-C₆-cycloalkyl-C₁-C₆-alkyl, aryl-C₁-C₆-alkyl or        C₁-C₆-alkoxy-C₁-C₆-alkyl,        wherein said aryl-C₁-C₆-alkyl group is substituted, one or more        times, in the same way or differently, with R⁶;        R^(5′) is aryl-C₁-C₆-alkyl,        wherein said aryl-C₁-C₆-alkyl group is substituted, one or more        times, in the same way or differently, with R⁶;        each occurrence of R⁶ may be the same or different and is        independently a hydrogen atom, a methyl group;        each occurrence of R⁷ and R^(7′) may be the same or different        and is independently a hydrogen atom, or a C₁-C₆-alkyl,        C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₆-cycloalkyl,        C₃-C₆-cycloalkyl-C₁-C₆-alkyl, C₃-C₆-cycloalkenyl, aryl,        aryl-C₁-C₆-alkyl, heteroaryl, 3- to 8-membered heterocyclic        ring, 3- to 8-membered heterocyclyl-C₁-C₆-alkyl, or        heteroaryl-C₁-C₆-alkyl;        each occurrence of R⁸ is independently a halogen atom, or nitro,        hydroxy, cyano, formyl, acetyl, amino, C₁-C₆-alkyl,        C₁-C₆-alkoxy, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₆-cycloalkyl,        C₃-C₆-cycloalkyl-C₁-C₆-alkyl, C₁-C₆-cycloalkenyl, aryl,        aryl-C₁-C₆-alkyl, heteroaryl, 3- to 8-membered heterocyclic        ring, heterocyclyl-C₁-C₆-alkyl, or heteroaryl-C₁-C₆-alkyl;        n is an integer of 1 and m is an integer of 1;        or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate,        or a salt thereof, in particular a physiologically acceptable        salt, or a mixture of same.

In accordance with a fifth aspect, the present invention coverscompounds of general formula (I), supra, in which:

R¹ represents —(CH₂)_(n)—(CHR⁴)—(CH₂)_(m)—N(R)(R);R² represents a heteroaryl of structure:

in which:

-   -   * represents the point of attachment of said heteroaryl with the        rest of the structure of general formula (I), and    -   Z represents N or C—R⁶;        R³ is methyl;        R⁴ is hydroxy;        R⁵ is a hydrogen atom, or a C₁-C₆-alkyl,        C₃-C₆-cycloalkyl-C₁-C₆-alkyl, aryl-C₁-C₆-alkyl or        C₁-C₆-alkoxy-C₁-C₆-alkyl,        wherein said aryl-C₁-C₆-alkyl group is substituted, one or more        times, in the same way or differently, with R⁶;        R^(5′) is aryl-C₁-C₆-alkyl,        wherein said aryl-C₁-C₆-alkyl group is substituted, one or more        times, in the same way or differently, with R⁶;        each occurrence of R⁶ may be the same or different and is        independently a hydrogen atom, a methyl group;        each occurrence of R⁷ and R^(7′) may be the same or different        and is independently a hydrogen atom, or a C₁-C₆-alkyl,        C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₆-cycloalkyl,        C₃-C₆-cycloalkyl-C₁-C₆-alkyl, C₃-C₆-cycloalkenyl, aryl,        aryl-C₁-C₆-alkyl, heteroaryl, 3- to 8-membered heterocyclic        ring, 3- to 8-membered heterocyclyl-C₁-C₆-alkyl, or        heteroaryl-C₁-C₆-alkyl;        each occurrence of R⁸ is independently a halogen atom, or nitro,        hydroxy, cyano, formyl, acetyl, amino, C₁-C₆-alkyl,        C₁-C₆-alkoxy, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₆-cycloalkyl,        C₃-C₆-cycloalkyl-C₁-C₆-alkyl, C₁-C₆-cycloalkenyl, aryl,        aryl-C₁-C₆-alkyl, heteroaryl, 3- to 8-membered heterocyclic        ring, heterocyclyl-C₁-C₆-alkyl, or heteroaryl-C₁-C₆-alkyl;        n is an integer of 1 and m is an integer of 1;        or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate,        or a salt thereof, in particular a physiologically acceptable        salt, or a mixture of same.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein

R¹ represents —(CH₂)_(n)—(CHR⁴)—(CH₂)_(m)N(R⁵)(R);

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein

R² represents a heteroaryl of structure

optionally substituted with 1, 2 or 3 R⁶ groups,

in which:

-   -   * represents the point of attachment of said heteroaryl with the        rest of the structure of general formula (I),    -   X represents N or C—R⁶,    -   X′ represents O, S, NH, N—R⁶, N or C—R⁶,    -   with the proviso that when X and X′ are both C—R⁶, then one C—R⁶        is C—H;

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein

R³ is methyl;

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein

R⁴ is hydroxy;

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein

R⁵ is a hydrogen atom, or a C₁-C₆-alkyl, C₃-C₆-cycloalkyl-C₁-C₆-alkyl,aryl-C₁-C₆-alkyl or C₁-C₆-alkoxy-C₁-C₆-alkyl,wherein said aryl-C₁-C₆-alkyl group is substituted, one or more times,in the same way or differently, with R⁶;

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein

R^(5′) is aryl-C₁-C₆-alkyl,wherein said aryl-C₁-C₆-alkyl group is substituted, one or more times,in the same way or differently, with R⁶;

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein

each occurrence of R⁶ may be the same or different and is independentlya hydrogen atom, a halogen atom, C₁-C₆-alkyl, C₂-C₆-alkenyl,C₂-C₆-alkynyl, C₃-C₆-cycloalkyl, C₃-C₆-cycloalkyl-C₁-C₆-alkyl, aryl,aryl-C₁-C₆-alkyl, heteroaryl, heteroaryl-C₁-C₆-alkyl, 3- to 8-memberedheterocyclic ring, 3- to 8-membered heterocyclyl-C₁-C₆-alkyl,—C₁-C₆-alkyl-OR⁷, —C₁-C₆-alkyl-SR⁷, —C₁-C₆-alkyl-N(R⁷)(R^(7′)),—C₁-C₆-alkyl-C(═O)R⁷, —CN, —C(═O)OR⁷, —C(═O)N(R⁷)(R^(7′)), —OR⁷, —SR⁷,—N(R⁷)(R^(7′)), or —NR⁷C(═O)R⁷ each of which may be optionallysubstituted with 1 or more R⁸ groups;

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein

each occurrence of R⁷ and R^(7′) may be the same or different and isindependently a hydrogen atom, or a C₁-C₆-alkyl, C₂-C₆-alkenyl,C₂-C₆-alkynyl, C₃-C₆-cycloalkyl, C₃-C₆-cycloalkyl-C₁-C₆-alkyl,C₃-C₆-cycloalkenyl, aryl, aryl-C₁-C₆-alkyl, heteroaryl, 3- to 8-memberedheterocyclic ring, 3- to 8-membered heterocyclyl-C₁-C₆-alkyl, orheteroaryl-C₁-C₆-alkyl;

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein

each occurrence of R⁸ is independently a halogen atom, or nitro,hydroxy, cyano, formyl, acetyl, amino, C₁-C₆-alkyl, C₁-C₆-alkoxy,C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₆-cycloalkyl,C₃-C₆-cycloalkyl-C₁-C₆-alkyl, C₁-C₆-cycloalkenyl, aryl,aryl-C₁-C₆-alkyl, heteroaryl, 3- to 8-membered heterocyclic ring,heterocyclyl-C₁-C₆-alkyl, or heteroaryl-C₁-C₆-alkyl;

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein

n is an integer of 1 and m is an integer of 1;

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein

R² represents a heteroaryl of structure:

in which:

-   -   * represents the point of attachment of said heteroaryl with the        rest of the structure of general formula (I);

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein

R⁵ is a hydrogen atom, or a C₁-C₆-alkyl, C₃-C₆-cycloalkyl-C₁-C₆-alkyl,aryl-C₁-C₆-alkyl or C₁-C₆-alkoxy-C₁-C₆-alkyl,wherein said aryl-C₁-C₆-alkyl group is substituted, one or more times,in the same way or differently, with R⁶;

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (II), wherein

R^(5′) is aryl-C₁-C₆-alkyl,wherein said aryl-C₁-C₆-alkyl group is substituted, one or more times,in the same way or differently, with R⁶;

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein

each occurrence of R⁶ may be the same or different and is independentlya hydrogen atom, a methyl group;

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein

R² represents a heteroaryl of structure:

in which:

-   -   represents the point of attachment of said heteroaryl with the        rest of the structure of general formula (I);

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein

R² represents a heteroaryl of structure:

in which:

-   -   * represents the point of attachment of said heteroaryl with the        rest of the structure of general formula (I), and    -   Z represents N or C—R⁶;

It is to be understood that the present invention relates to anysub-combination within any embodiment of the present invention ofcompounds of general formula (I), supra.

In a further aspect, the present invention covers compounds of generalformula (I) which are disclosed in the Example section of this text,infra.

In accordance with another aspect, the present invention covers a methodof preparing compounds of the present invention, the method comprisingthe steps as described herein.

In accordance with a further aspect, the present invention coversintermediate compounds which are useful in the preparation of compoundsof the present invention of general formula (I), particularly in themethod described herein. In particular, the present invention coverscompounds of general formula (XI):

in which R1 and R3 are as defined supra as for general formula (I).

In accordance with yet another aspect, the present invention covers theuse of the intermediate compounds of general formula (XI), supra, forthe preparation of the compounds of the present invention of generalformula (I), supra.

EXPERIMENTAL General Preparative Methods

The particular process to be utilized in the preparation of thecompounds used in this embodiment of the invention depends upon thespecific compound desired. Such factors as the selection of the specificsubstituents play a role in the path to be followed in the preparationof the specific compounds of this invention. Those factors are readilyrecognized by one of ordinary skill in the art.

The compounds of the invention may be prepared by use of known chemicalreactions and procedures. Nevertheless, the following generalpreparative methods are presented to aid the reader in synthesizing thecompounds of the present invention, with more detailed particularexamples being presented below in the experimental section describingthe working examples.

The compounds of the invention can be made according to conventionalchemical methods, and/or as disclosed below, from starting materialswhich are either commercially available or producible according toroutine, conventional chemical methods. General methods for thepreparation of the compounds are given below, and the preparation ofrepresentative compounds is specifically illustrated in examples.

Synthetic transformations that may be employed in the synthesis ofcompounds of this invention and in the synthesis of intermediatesinvolved in the synthesis of compounds of this invention are known by oraccessible to one skilled in the art. Collections of synthetictransformations may be found in compilations, such as:

-   J. March. Advanced Organic Chemistry, 4th ed.; John Wiley: New York    (1992)-   R. C. Larock. Comprehensive Organic Transformations, 2nd ed.;    Wiley-VCH: New York (1999)-   F. A. Carey; R. J. Sundberg. Advanced Organic Chemistry, 2nd ed.;    Plenum Press: New York (1984)-   T. W. Greene; P. G. M. Wuts. Protective Groups in Organic Synthesis,    3rd ed.; John Wiley: New York (1999)-   L. S. Hegedus. Transition Metals in the Synthesis of Complex Organic    Molecules, 2nd ed.; University Science Books: Mill Valley, Calif.    (1994)-   L. A. Paquette, Ed. The Encyclopedia of Reagents for Organic    Synthesis; John Wiley: New York (1994)-   A. R. Katritzky; O. Meth-Cohn; C. W. Rees, Eds. Comprehensive    Organic Functional Group Transformations; Pergamon Press: Oxford, UK    (1995)-   G. Wilkinson; F. G A. Stone; E. W. Abel, Eds. Comprehensive    Organometallic Chemistry; Pergamon Press: Oxford, UK (1982)-   B. M. Trost; I. Fleming. Comprehensive Organic Synthesis; Pergamon    Press: Oxford, UK (1991)-   A. R. Katritzky; C. W. Rees Eds. Comprehensive Heterocylic    Chemistry; Pergamon Press: Oxford, UK (1984)-   A. R. Katritzky; C. W. Rees; E. F. V. Scriven, Eds. Comprehensive    Heterocylic Chemistry II; Pergamon Press: Oxford, UK (1996)-   C. Hansch; P. G. Sammes; J. B. Taylor, Eds. Comprehensive Medicinal    Chemistry: Pergamon Press: Oxford, UK (1990).

In addition, recurring reviews of synthetic methodology and relatedtopics include Organic Reactions; John Wiley: New York; OrganicSyntheses; John Wiley: New York; Reagents for Organic Synthesis: JohnWiley: New York; The Total Synthesis of Natural Products; John Wiley:New York; The Organic Chemistry of Drug Synthesis; John Wiley: New York;Annual Reports in Organic Synthesis; Academic Press: San Diego Calif.;and Methoden der Organischen Chemie (Houben-Weyl); Thieme: Stuttgart,Germany. Furthermore, databases of synthetic transformations includeChemical Abstracts, which may be searched using either CAS OnLine orSciFinder, Handbuch der Organischen Chemie (Beilstein), which may besearched using SpotFire, and REACCS.

In the following, “PG” refers to a suitable protecting group, well-knownto the person skilled in the art, e.g. from T. W. Greene; P. G. M. Wuts.Protective Groups in Organic Synthesis, 3rd ed.; John Wiley: New York(1999).

In Reaction Scheme 1, vanillin acetate can be converted to intermediate(111) via nitration conditions such as neat fuming nitric acid or nitricacid in the presence of another strong acid such as sulfuric acid.Hydrolysis of the acetate in intermediate (III) would be expected in thepresence of bases such as sodium hydroxide, lithium hydroxide, orpotassium hydroxide in a protic solvent such as methanol. Protection ofintermediate (IV) to generate compounds of Formula (V) (PG=protectinggroup, well-known to the person skilled in the art) could beaccomplished by standard methods (Greene, T. W.; Wuts, P. G. M.;Protective Groups in Organic Synthesis; Wiley & Sons: New York, 1999).Conversion of compounds of formula (V) to those of formula (VI) can beachieved using ammonia in the presence of iodine in an aprotic solventsuch as THF or dioxane. Reduction of the nitro group in formula (VI)could be accomplished using iron in acetic acid or hydrogen gas in thepresence of a suitable palladium, platinum or nickel catalyst.Conversion of compounds of formula (VII) to the imidazoline of formula(VIII) is best accomplished using ethylenediamine in the presence of acatalyst such as elemental sulfur with heating. The cyclization ofcompounds of formula (VIII) to those of formula (IX) is accomplishedusing cyanogen bromide in the presence of an amine base such astriethylamine, diisopropylethylamine, or pyridine in a halogenatedsolvent such as DCM or dichloroethane. Removal of the protecting groupin formula (IX) will be dependent on the group selected and can beaccomplished by standard methods (Greene, T. W.; Wuts, P. G. M.;Protective Groups in Organic Synthesis; Wiley & Sons: New York, 1999).Alkylation of the phenol in formula (X) can be achieved using a basesuch as caesium carbonate, sodium hydride, or potassium t-butoxide in apolar aprotic solvent such as DMF or DMSO with introduction of a sidechain bearing an appropriate leaving group such as a halide, or asulfonate group, to provide compounds of formula (XI). Lastly, amides offormula (I) can be formed using activated esters such as acid chloridesand anhydrides or alternatively formed using carboxylic acids andappropriate coupling agents such as PYBOP, DCC, or EDCI in polar aproticsolvents.

In Reaction Scheme 2, a compound of formula (IV), prepared as describedabove, can be converted to a structure of formula (XII) using ammonia inthe presence of iodine in an aprotic solvent such as THF or dioxane.Alkylation of the phenol in formula (XII) can be achieved using a basesuch as caesium carbonate, sodium hydride, or potassium t-butoxide in apolar aprotic solvent such as DMF or DMSO with introduction of a sidechain bearing an appropriate leaving group such as a halide, or asulfonate group. Reduction of the nitro group in formula (XIII) could beaccomplished using iron in acetic acid or hydrogen gas in the presenceof a suitable palladium, platinum or nickel catalyst. Conversion ofcompounds of formula (XIV) to the imidazoline of formula (XV) is bestaccomplished using ethylenediamine in the presence of a catalyst such aselemental sulfur with heating. The cyclization of compounds of formula(XV) to those of formula (XVI) is accomplished using cyanogen bromide inthe presence of an amine base such as triethylamine,diisopropylethylamine, or pyridine in a halogenated solvent such as DCMor dichloroethane. Lastly, amides of formula (I) can be formed usingactivated esters such as acid chlorides and anhydrides or alternativelyformed using carboxylic acids and appropriate coupling agents such asPYBOP, DCC, or EDCI in polar aprotic solvents.

In Reaction Scheme 3, a compound of formula (X), prepared as describedabove, can be converted to amide (XVI) using activated esters such asacid chlorides and anhydrides or alternatively formed using carboxylicacids and appropriate coupling agents such as PYBOP, DCC, or EDCI inpolar aprotic solvents. This could then be converted to compounds offormula (I) using a base such as caesium carbonate, sodium hydride, orpotassium t-butoxide in a polar aprotic solvent such as DMF or DMSO withintroduction of a side chain bearing an appropriate leaving group suchas a halide, or a sulfonate group.

In Reaction Scheme 4, a compound of formula (IX), prepared as describedabove, can be converted to amide (XVII) using activated esters such asacid chlorides and anhydrides or alternatively formed using carboxylicacids and appropriate coupling agents such as PYBOP, DCC, or EDCI inpolar aprotic solvents. Removal of the protecting group in formula(XVII) will be dependent on the group selected and can be accomplishedby standard methods (Greene, T. W.; Wuts, P. G. M.; Protective Groups inOrganic Synthesis; Wiley & Sons: New York, 1999). Alkylation of thephenol in formula (XVI) can be achieved using a base such as caesiumcarbonate, sodium hydride, or potassium t-butoxide in a polar aproticsolvent such as DMF or DMSO with introduction of a side chain bearing anappropriate leaving group such as a halide, or a sulfonate group.

In Reaction Scheme 5, a compound of formula XVIII can be converted tothe bis chloride compound of formula XIX using chlorinating agents suchas POCl₃ or COCl₂ in aprotic solvents. The chloride thus obtained can beconverted to imidazolines of formula XXI through reaction withappropriate quantities of ethanolamine or a suitably protectedsubstitute, followed by activation with a suitable activating agent suchas a sulfonyl chloride, PPh₃, or an halogenating agent such as SOCl₂.Chloride XXI can be converted to amine XXII through the use of anysource of nucleophilic amine such as ammonia, phthalimide, or protectedamines such as benzyl amine.in a polar solvent such as DMF or DMSO.Formation of the phenol depicted in formula X can be accomplishedthrough deprotection of the methyl ether using any of the conditionsoutlined in the literature (Greene, T. W.; Wuts, P. G. M.; ProtectiveGroups in Organic Synthesis; Wiley & Sons: New York, 1999).

In order that this invention may be better understood, the followingexamples are set forth. These examples are for the purpose ofillustration only, and are not to be construed as limiting the scope ofthe invention in any manner. All publications mentioned herein areincorporated by reference in their entirety.

ABBREVIATIONS AND ACRONYMS

A comprehensive list of the abbreviations used by organic chemists ofordinary skill in the art appears in The ACS Style Guide (third edition)or the Guidelines for Authors for the Journal of Organic Chemistry. Theabbreviations contained in said lists, and all abbreviations utilized byorganic chemists of ordinary skill in the art are hereby incorporated byreference. For purposes of this invention, the chemical elements areidentified in accordance with the Periodic Table of the Elements, CASversion, Handbook of Chemistry and Physics, 67th Ed., 1986-87.

More specifically, when the following abbreviations are used throughoutthis disclosure, they have the following meanings:

-   -   acac acetylacetonate    -   Ac₂O acetic anhydride    -   AcO (or OAc) acetate    -   anh anhrous    -   aq aqueous    -   Ar aryl    -   atm atmosphere    -   9-BBN 9-borabicyclo[3.3.1]nonyl    -   BINAP 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl    -   Bn benzyl    -   bp boiling point    -   br s broad singlet    -   Bz benzoyl    -   BOC tert-butoxycarbonyl    -   n-BuOH n-butanol    -   t-BuOH tert-butanol    -   t-BuOK potassium tert-butoxide    -   C Celsius    -   calcd calculated    -   CAN ceric ammonium nitrate    -   Cbz carbobenzyloxy    -   CDI carbonyl diimidazole    -   CD₃OD methanol-d₄    -   Celite® diatomaceous earth filter agent, Celite® Corp.    -   CI-MS chemical ionization mass spectroscopy    -   ¹³C NMR carbon-13 nuclear magnetic resonance    -   m-CPBA meta-chloroperoxybenzoic acid    -   d doublet    -   dd doublet of doublets    -   DABCO 1,4-diazabicyclo[2.2.2]octane    -   DBU 1,8-diazabicyclo[5.4.0]undec-7-ene    -   DCC N,N′-dicyclohexylcarbodiimide    -   DCM dichloromethane    -   DEAD diethyl azodicarboxylate    -   dec decomposition    -   DIA diisopropylamine    -   DIBAL diisobutylaluminum hydride    -   DMAP 4-(N,N-dimethylamino)pyridine    -   DME 1,2-dimethoxyethane    -   DMF N,N-dimethylformamide    -   DMSO dimethylsulfoxide    -   E entgegen (configuration)    -   EDCI or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide    -   EDCI.HCl hydrochloride    -   ee enantiomeric excess    -   EI electron impact    -   ELSD evaporative light scattering detector    -   equiv equivalent    -   ES-MS electrospray mass spectroscopy    -   EtOAc ethyl acetate    -   EtOH ethanol (100%)    -   EtSH ethanethiol    -   Et₂O diethyl ether    -   Et₃N triethylamine    -   Fmoc 9-fluorenylmethoxycarbonyl    -   GC gas chromatography    -   GC-MS gas chromatography-mass spectroscopy    -   h hour, hours    -   hex hexanes, or hexane    -   ¹H NMR proton nuclear magnetic resonance    -   HMPA hexamethylphosphoramide    -   HMPT hexamethylphosphoric triamide    -   HOBT hydroxybenzotriazole    -   HPLC high performance liquid chromatography    -   insol insoluble    -   IPA isopropylamine    -   iPrOH isopropylalcohol    -   IR infrared    -   J coupling constant (NMR spectroscopy)    -   L liter    -   LAH lithium aluminum hydride    -   LC liquid chromatography    -   LC-MS liquid chromatography-mass spectrometry    -   LDA lithium diisopropylamide    -   M mol L⁻¹ (molar)    -   m multiplet    -   m meta    -   MeCN acetonitrile    -   MeOH methanol    -   MHz megahertz    -   min minute, minutes    -   μL microliter    -   mL milliliter    -   μM micromolar    -   mol mole    -   mp melting point    -   MS mass spectrum, mass spectrometry    -   Ms methanesulfonyl    -   m/z mass-to-charge ratio    -   N equiv L⁻¹ (normal)    -   NBS N-bromosuccinimide    -   nM nanomolar    -   NMM 4-methylmorpholine    -   NMR Nuclear Magnetic Resonance    -   o ortho    -   obsd observed    -   p para    -   p page    -   pp pages    -   PdCl₂dppf        [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)    -   Pd(OAc)₂ palladium acetate    -   pH negative logarithm of hydrogen ion concentration    -   Ph phenyl    -   pK negative logarithm of equilibrium constant    -   pK_(a) negative logarithm of equilibrium constant for        association    -   PPA poly(phosphoric acid)    -   PS-DIEA Polystyrene-bound diisopropylethylamine    -   PyBOP benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium        hexafluorophosphate    -   q quartet    -   rac racemic    -   R rectus (configurational)    -   rel refers to a compound in which one chiral center is not        defined, said chiral center being in the presence of one or more        other chiral centers which are defined    -   R_(f) retardation factor (TLC)    -   RT retention time (HPLC)    -   rt room temperature    -   s singlet    -   S sinister (configurational)    -   t triplet    -   TBDMS, TBP tert-butyldimethylsilyl    -   TBDPS, TPS tert-butyldiphenylsilyl    -   TEA triethylamine    -   THF tetrahydrofuran    -   Tf trifluoromethanesulfonyl (triflyl)    -   TFA trifluoroacetic acid    -   TFFH Fluoro-N,N,N′,N′-tetramethylformamidinium        hexafluorophosphate    -   TLC thin layer chromatography    -   TMAD N,N,N′,N′-tetramethylethylenediamine    -   TMSCl trimethylsilyl chloride    -   Ts p-toluenesulfonyl    -   v/v volume to volume ratio    -   w/v weight to volume ratio    -   w/w weight to weight ratio    -   Z zusammen (configuration)

Specific Experimental Descriptions

Analytical HPLC-MS Conditions:

HPLC-MS-data given in the subsequent specific experimental descriptionsrefer to the following conditions:

System: Waters Acquity UPLC-MS: Binary Solvent Manager, SampleManager/Organizer, Column Manager, PDA, ELSD, SQD 3001 or ZQ4000 System:Waters Acquity UPLC-MS: Binary Solvent Manager, SampleManager/Organizer, PDA, ELSD, Column: Acquity UPLC BEH C18 1.7 50 × 2.1mm Solvent: A1 = H2O + 0.1% HCOOH A2 = H2O + 0.2% NH3 B1 = AcetonitrileGradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B Flow: 0.8 mL/minTemperatuer: 60° C. Injektion: 2.0 μl Detection: DAD scan range 210-400nm

Method 1:

99% 0.1% aqueous Formic Acid: 1% CH₃CN to 1% 0.1% aqueous Formic Acid:99% CH₃CN over 1.6 min.; 1% 0.1% aqueous Formic Acid: 99% CH₃CN over 1.6min. for 0.4 min.

Method 2:

99% 0.2% aqueous Ammonia: 1% CH₃CN to 1% 0.1% aqueous Ammonia: 99% CH₃CNover 1.6 min.; 1% 0.1% aqueous Ammonia: 99% CH₃CN over 1.6 min. for 0.4min.

Unless otherwise stated, analytical HPLC utilized Method 2.

Preparative HPLC Conditions:

Unless otherwise noted, “Purification by preparative HPLC” in thesubsequent specific experimental descriptions refers to the followingconditions:

Analytics:

System: Waters Aqcuity UPLC-MS: Binary Solvent Manager, SampleManager/Organizer, Column Manager, PDA, ELSD, SQD 3001 Column: AqcuityBEH C18 1.7 50 × 2.1 mm Solvent: A = H₂O + 0.1% HCOOH B = AcetonitrileGradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B Flow: 0.8 mL/minTemperature: 60° C. Injection: 2.0 μl Detection: DAD scan range 210-400nm MS ESI+, ESI−, scan range 160-1000 m/z ELSD

Preparation:

System: Waters Autopurificationsystem: Pump 2545, Sample Manager 2767,CFO, DAD 2996, ELSD 2424, SQD 3001 Column: XBrigde C18 5 μm 100 × 30 mmSolvent: A = H₂O + 0.1% HCOOH B = Acetonitril Gradient: 0-1 min 1% B,1-8 min 1-99% B, 8-10 min 99% B Flow: 50 mL/min Temperature: RTSolution: Max. 250 mg/2.5 mL DMSO o. DMF Injection: 1 × 2.5 mLDetection: DAD scan range 210-400 nm MS ESI+, ESI−, scan range 160-1000m/z

Chiral HPLC Conditions:

Chiral HPLC-data given in the subsequent specific experimentaldescriptions refer to the following conditions:

Analytics:

System: Dionex: Pump 680, ASI 100, Waters: UV-Detektor 2487 Column:Chiralpak IC 5 μm 150 × 4.6 mm Solvent: Hexan/Ethanol 80:20 + 0.1%Diethylamin Flow: 1.0 mL/min Temperature: 25° C. Solution: 1.0 mg/mLEtOH/MeOH 1:1 Injection: 5.0 μl Detection: UV 280 nm

Preparation:

System: Agilent: Prep 1200, 2xPrep Pump, DLA, MWD, Prep FC, ESA: CoronaColumn: Chiralpak IC 5 μm 250 × 30 mm Solvent: Hexan/Ethanol 80:20 +0.1% Diethylamin Flow: 40 mL/min Temperature: RT Solution: 660 mg/5.6 mLEtOH Injection: 8 × 0.7 mL Detection: UV 280 nm

Preparative MPLC:

Preparative medium pressure liquid chromatography (MPLC) was carried outby standard silica gel “flash chromatography” techniques (e.g., Still etal., 1978), or by using silica gel cartridges and devices such as theFlashmaster or Biotage Flash systems.

Unless otherwise stated, MPLC purifications were conducted using a FlashMaster II chromatograph equipped with an Isolute Flash NH₂ reverse phasecolumn eluting with a mixed solvent gradient (100% CH₂Cl₂ for 3 min.,gradient to 90% CH₂Cl₂: 10% MeOH over 12 minutes; gradient to 80%CH₂Cl₂: 20% MeOH over 20 min.; gradient to 70% CH₂Cl₂: 30% MeOH over 10min.; and gradient to 50% CH₂Cl₂: 50% MeOH over 15 min.) at the flowrate recommended for the column size (i.e., 5 g column, 10 mL/min.; 50 gcolumn, 30 ml/min.). Eluant was monitored with a UV detector at 254 nm.

Determination of Optical Rotation Conditions:

Optical rotations were measured in DMSO, at 589 nm wavelength, 20° C.,concentration 1.0000 g/100 mL, intergration time 10 s, film thickness100.00 mm.

The structures of compounds of this invention were confirmed using oneor more of the following procedures.

NMR

NMR spectra were acquired for each compound and were consistent with thestructures shown.

Routine one-dimensional NMR spectroscopy was performed on either 300 or400 MHz Varian Mercury-plus spectrometers. The samples were dissolved indeuterated solvents. Chemical shifts were recorded on the ppm scale andwere referenced to the appropriate solvent signals, such as 2.49 ppm forDMSO-d₆, 1.93 ppm for CD₃CN, 3.30 ppm for CD₃OD, 5.32 ppm for CD₂Cl₂ and7.26 ppm for CDCl₃ for ¹H spectra.

The percentage yields reported in the following examples are based onthe starting component that was used in the lowest molar amount. Air andmoisture sensitive liquids and solutions were transferred via syringe orcannula, and introduced into reaction vessels through rubber septa.

Commercial grade reagents and solvents were used without furtherpurification. The term “concentrated under reduced pressure” refers touse of a Buchi rotary evaporator at approximately 15 mm of Hg. Alltemperatures are reported uncorrected in degrees Celsius (° C.).

Thin layer chromatography (TLC) was performed on pre-coated glass-backedsilica gel 60 A F-254 250 μm plates.

Reactions employing microwave irradiation were run with a BiotageInitator® microwave oven optionally equipped with a robotic unit. Thereported reaction times employing microwave heating are intended to beunderstood as fixed reaction times after reaching the indicated reactiontemperature.

The percentage yields reported in the following examples are based onthe starting component that was used in the lowest molar amount. Air andmoisture sensitive liquids and solutions were transferred via syringe orcannula, and introduced into reaction vessels through rubber septa.Commercial grade reagents and solvents were used without furtherpurification. The term “concentrated in vacuo” refers to use of a Buchirotary evaporator at a minimum pressure of approximately 15 mm of Hg.All temperatures are reported uncorrected in degrees Celsius (° C.).

Names of compounds were generated using ACD/Name Batch version 12.01. Insome cases generally accepted names of commercially available reagentswere used.

SYNTHESIS OF INTERMEDIATES Intermediate A Preparation of2-aminopyrimidine-5-carboxylic acid

Sodium (1Z)-2-(dimethoxymethyl)-3-methoxy-3-oxoprop-1-en-1-olate wasprepared as described by Zhichkin (Zhichkin et al., 2002).

Sodium (1Z)-2-(dimethoxymethyl)-3-methoxy-3-oxoprop-1-en-1-olate (1.37g, 7.8 mmol) was diluted in DMF (12 mL), and guanidine hydrochloride(640 mg, 6.7 mmol) was added. The mixture was stirred at 100° C. for 1h, then was cooled to rt and diluted with water. Methyl2-aminopyrimidine-5-carboxylate precipitated as a light yellow solid,which was isolated by vacuum filtration (510 mg, 50%): ¹H NMR (DMSO-d₆)δ: 8.67 (s, 2H), 7.56 (br s, 2H), 3.79 (s, 3H).

Methyl 2-aminopyrimidine-5-carboxylate (300 mg, 2.0 mmol) was diluted inmethanol (5 mL) containing a few drops of water. Lithium hydroxide (122mg, 5.1 mmol) was added, and the reaction mixture was stirred at 60° C.overnight. The mixture was concentrated under reduced pressure, thendiluted in water and adjusted to pH 4 with 1 M HCl.2-Aminopyrimidine-5-carboxylic acid precipitated as a white solid, whichwas isolated by vacuum filtration (244 mg, 90%): ¹H NMR (DMSO-d₆) δ:12.73 (1H, br s), 8.63 (2H, s), 7.44 (2H, br s).

Intermediate B Preparation of 4-(3-chloropropylmorholine hydrochloride

To a solution of 1-bromo-3-chloropropane (45 g, 0.29 mol) in toluene(100 mL) was added morpholine (38 g, 0.44 mol). The solution was stirredat 84° C. for 3 h, during which time a precipitate formed. After coolingto rt, the precipitate was isolated by vacuum filtration, washed withether, and the solid was discarded. The mother liquor was acidified withHCl (4 M in dioxane, 72 mL, 0.29 mol), which caused the desired productto precipitate as an HCl salt. Solvent was removed under reducedpressure, and the resultant solid was dried to afford the title compound(53 g, 90%): ¹H NMR (DMSO-d₆) δ: 11.45 (1H, br s), 3.94-3.77 (4H, m),3.74 (2H, t), 3.39 (2H, m), 3.15 (2H, m), 3.03 (2H, m), 2.21 (2H, m).

Intermediate B Preparation of 6-amino-2-methyinicotinic acid

A suspension of 6-amino-2-methylnicotinonitrile (1.0 g, 7.5 mmol) in anaqueous KOH solution (20%, 12 mL) was heated at the reflux temperaturefor 3 days. After this time, it was cooled to room temperature,neutralized with concentrated HCl, filtered and dried to give thedesired product which was used without further purification (1.1 g,96%).

Intermediate C Preparation of4-[(2-oxido-1,3,2-dioxathiolan-4-yl)methyl]morpholine hydrochloride

3-Morpholin-4-ylpropane-1,2-diol (2.1 g, 9.07 mmol) was dissolved in DCM(15 mL) and cooled to 0° C. The cooled solution was treated with thionylchloride (1.81 mL, 24.8 mmol) and then heated at the reflux temperaturefor 1 h. The reaction mixture was then concentrated under reducedpressure to give a solid (2.5 g, 97%): ¹H NMR (DMSO-d₆) δ: 11.4 (1H, brs), 5.64-5.55 (1H, m) 4.82 (1H, dd), 4.50 (1H, dd), 4.02-3.71 (4H, m),3.55-3.33 (4H, m), 3.26-3.06 (2H, br s).

Intermediate D Preparation of8-(benzyloxy)-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine Step1: Preparation of 4-formyl-2-methoxy-3-nitrophenyl acetate

Fuming nitric acid (2200 mL) under nitrogen was cooled to 0° C. at whichtime vanillin acetate (528 g, 2.7 mol) was added portionwise, keepingthe internal temperature below 10° C. After 2 h the resulting mixturewas poured over ice with stirring. The slurry was filtered and theresulting solids were washed with water (3×100 mL) and air-dried. After2 days the solids were heated in DCM (3000 mL) until completedissolution. The solution was allowed to cool to room temperature whilehexanes (3000 mL) was added dropwise. The solids were filtered, washedwith hexanes (500 mL) and air dried to give4-formyl-2-methoxy-3-nitrophenyl acetate (269 g, 41%): ¹H NMR, (DMSO-d₆)δ: 9.90 (s, 1H), 7.94 (d, 1H), 7.75 (d, 1H), 3.87 (s, 3H), 2.40 (s, 3H).

Step 2: Preparation of 4-hydroxy-3-methoxy-2-nitrobenzaldehyde

A mixture of 4-formyl-2-methoxy-3-nitrophenyl acetate 438 g (1.8 mol)and potassium carbonate (506 g, 3.7 mol) in MeOH (4000 mL) was stirredat room temperature for 16 h. The reaction mixture was concentratedunder reduced pressure to afford a viscous oil. This was dissolved inwater, acidified using a solution of HCl (2 N) and extracted with EtOAc.The organic layer was washed with a saturated sodium chloride solution,dried (magnesium sulfate) and filtered. The solvent was concentratedunder reduced pressure to ⅓ volume and the resulting solids werefiltered and air-dried to give 4-hydroxy-3-methoxy-2-nitrobenzaldehyde(317 g, 88%): ¹H NMR (DMSO-d₆) δ: 9.69 (1H, s), 7.68 (1H, d), 7.19 (1H,d), 3.82 (3H, s).

Step 3: Preparation of 4-(benzyloxy)-3-methoxy-2-nitrobenzaldehyde

4-Hydroxy-3-methoxy-2-nitrobenzaldehyde (155 g, 786 mmol) was dissolvedin DMF (1500 mL) and the stirred solution was treated with potassiumcarbonate (217 g, 1.57 mol) followed by benzyl bromide (161 g, 0.94mol). After stirring for 16 h the reaction mixture was concentratedunder reduced pressure and separated between water (2 L) and EtOAc (2L). The organic layer was washed with a saturated sodium chloridesolution (3×2 L), dried (anh. sodium sulfate) and concentrated underreduced pressure. The resulting solids were triturated with Et₂O (1 L)to give 4-(benzyloxy)-3-methoxy-2-nitrobenzaldehyde (220 g, 97%): ¹H NMR(DMSO-d₆) δ: 9.77 (1H, s), 7.87 (1H, d), 7.58 (1H, d), 7.51 (1H, m),7.49 (1H, m), 7.39 (3H, m), 5.36 (2H, s), 3.05 (3H, s).

Step 4.: Preparation of 4-(benzyloxy)-3-methoxy-2-nitrobenzonitrile

Iodine (272 g, 1.1 mmol) was added to a mixture of4-(benzyloxy)-3-methoxy-2-nitrobenzaldehyde (220 g, 766 mmol) andammonium hydroxide (28% solution, 3 L) dissolved in THF (5 L). After 16h the reaction mixture was treated with sodium sulfite (49 g, 383 mmol)and concentrated under reduced pressure to afford a thick slurry. Theslurry was filtered, washed with water (250 mL) and dried to afford4-(benzyloxy)-3-methoxy-2-nitrobenzonitrile as a solid (206 g, 95%): ¹HNMR (DMSO-d₆) δ: 7.89 (1H, d), 7.59 (1H, d), 7.49 (2H, m), 7.40 (3H, m),5.35 (2H, s), 3.91 (3H, s).

Step 5: Preparation of 2-amino-4-(benzyloxy)-3-methoxybenzonitrile

A degassed solution of 4-(benzyloxy)-3-methoxy-2-nitrobenzonitrile (185g, 651 mmol) in glacial acetic acid (3500 mL) and water (10 mL) wascooled to 5° C. and treated with iron powder (182 g, 3.25 mol). After 3days the reaction mixture was filtered through Celite, and the filtrateconcentrated under reduced pressure. The oil, thus obtained, was treatedwith a saturated sodium chloride solution, neutralized with a sodiumbicarbonate solution and extracted into CH₂Cl₂. The resulting emulsionwas filtered through Celite after which the organic layer was separated,washed with a saturated sodium chloride solution, dried (anh. sodiumsulfate) and concentrated under reduced pressure to afford2-amino-4-(benzyloxy)-3-methoxybenzonitrile as a solid (145 g, 88%): ¹HNMR (DMSO-d₆) δ: 7.32-7.44 (5H, m), 7.15 (1H, d), 6.47 (1H, d), 5.69(2H, s), 5.15 (2H, s), 3.68 (3H, s).

Step 6: Preparation of3-(benzyloxy)-6-(4,5-dihydro-1H-imidazol-2-yl)-2-methoxyaniline

A mixture of 2-amino-4-(benzyloxy)-3-methoxybenzonitrile (144 g, 566mmol) and sulfur (55 g, 1.7 mol) in ethylenediamine (800 mL) wasdegassed for 30 minutes then heated to 100° C.

After 16 h the reaction mixture was cooled to room temperature and thenfiltered. The filtrate was concentrated under reduced pressure, dilutedwith a saturated sodium bicarbonate solution and extracted with EtOAc.The organic layer was washed with brine, dried (sodium sulfate),filtered and concentrated under reduced pressure. The resulting solidswere recrystallized from EtOAc and hexanes to afford3-(benzyloxy)-6-(4,5-dihydro-1H-imidazol-2-yl)-2-methoxyaniline (145 g,86%): ¹H NMR (DMSO-d₆) δ: 7.27-7.48 (5H, m), 7.14 (1H, d), 6.92 (2H, m),6.64 (1H, m), 6.32 (1H, d), 5.11 (2H, s), 3.67 (3H, s), 3.33 (2H, s).

Step 7: Preparation of8-(benzyloxy)-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine

A mixture of3-(benzyloxy)-6-(4,5-dihydro-1H-imidazol-2-yl)-2-methoxyaniline (100 g,336 mmol) and triethylamine (188 mL) in DCM (3 L) was cooled to 0° C.and treated with cyanogen bromide (78.4 g, 740 mmol). The reactionmixture was stirred and allowed to warm to room temperature gradually.After 16 h the reaction mixture was diluted with a solution of saturatedsodium bicarbonate and extracted with CH₂Cl₂. The organic layer waswashed 3 times with saturated bicarbonate solution followed by multiplewashes with brine. The organic layer was dried (sodium sulfate) andconcentrated under reduced pressure to give a semi solid (130 g withtriethylamine salt contamination): ¹H NMR (DMSO-d₆) δ: 7.30-7.48 (7H,m), 5.31 (2H, s), 4.32 (2H, m), 4.13 (2H, m), 3.81 (3H, s).

Intermediate E Preparation of5-amino-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-8-olbis(trifluoroacetate)

3-(Benzyloxy)-6-(4,5-dihydro-1H-imidazol-2-yl)-2-methoxyaniline (30 g,93 mmol) was added portionwise over 1 h to a round bottom flaskcontaining TFA (400 mL) precooled with an ice bath. The reaction mixturewas heated to 60° C. and allowed to stir at this temperature for 17 h atwhich time it was cooled to rt and the reaction mixture concentratedunder reduced pressure. The resulting residue was taken up in DCM andhexanes and concentrated under reduced pressure. The material thusobtained was dissolved in a MeOH/CH₂Cl₂ solution (250 mL, 1:1) andconcentrated under reduced pressure. The resulting solid was driedovernight under vacuum with low heat to give5-amino-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-8-olbis(trifluoroacetate) (44.7 g, >100%): ¹H NMR (DMSO-d₆) δ: 7.61 (1H, m),6.87 (1H, m), 4.15 (2H, br t), 4.00 (2H, m), 3.64 (3H, s).

Intermediate F Preparation of7-Methoxy-8-[(2R)-oxiran-2-ylmethoxy]-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine

Step 1: Preparation of (R)-Glycidyl Methanesulfonate

A solution of (S)-(−)-glycidol (8.6 mL, 130 mmol) and triethylamine(36.2 mL, 260 mmol, 2.0 equiv.) in DMF (250 mL) was cooled over an icebath and methanesulfonyl chloride (10.1 mL, 130 mmol, 1.0 equiv.) wasadded dropwise. The mixture was stirred for 1.5 hr at room temperatureaffording a 0.47 M solution of (R)-glycidyl methanesulfonate in DMF,which was used without further purification.

Step 2: Preparation of7-Methoxy-8-[(2R)-oxiran-2-ylmethoxy]-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine

To a solution of5-amino-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-8-olbis(trifluoroacetate) (Intermediate E, 0.30 g, 0.65 mmol) in DMF (8 mL)was added caesium carbonate to generate a white suspension. Thesuspension was stirred at room temperature for 1.5 hr, then (R)-glycidylmethanesulfonate (Intermediate F, Step 1, 3.9 mL of 0.34 M solution inDMF, 1.30 mmol, 2.0 equiv.) was added, and the resulting solution wasstirred at 60° C. for 20 h. The resulting suspension was concentratedunder reduced pressure and the residue was treated separated between asaturated sodium bicarbonate solution (30 mL) and a 4:1CH₂Cl₂/isopropanol solution (30 mL). The aqueous phase was extractedwith a 4:1 CH₂Cl₂/isopropanol solution (30 mL). The combined organicphases were dried (anh. sodium sulfate) and concentrated under reducedpressure. The residue was purified using MPLC (Isolute Flash NH₂ reversephase column; 100% CH₂Cl₂ for 5 min., gradient to 95% CH₂Cl₂: 5% MeOHover 15 minutes; gradient to 90% CH₂Cl₂: 10% MeOH over 15 min.; gradientto 80% CH₂Cl₂: 20% MeOH over 15 min.; and gradient to 75% CH₂Cl₂: 25%MeOH over 15 min.) to give7-methoxy-8-[(2R)-oxiran-2-ylmethoxy]-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine(0.080 g, 43%): ¹H NMR (DMSO-d₆+1 drop TFA-d) δ 2.71 (dd, J=2.5, 4.8 Hz,1H), 2.85, (t, J=4.6 Hz, 1H), 3.34-3.40 (br m, 1H), 3.75 (s, 3H), 3.82(s, 3H), 4.30 (dd, J=6.6, 11.4 Hz, 1H), 4.10 (br t, J=9.7 Hz, 2H), 4.31(br t, J=9.7 Hz, 2H), 4.54 (dd, J=2.3, 11.6 Hz, 1H), 7.26 (d, J=9.4 Hz,1H), 7.84 (d, J=9.1 Hz, 1H).

Intermediate G Preparation of7-Methoxy-8-(oxiran-2-ylmethoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine

Step 1: Preparation of Racemic Glycidyl Methanesulfonate

Racemic glycidol methanesulfonate was synthesized in a manner analogousto Intermediate F, Step 1, substituting racemic gylcidol for(S)-(−)-glycidol The solution of racemic glycidyl methanesulfonate inDMF was used in further transformations without further purification.

Step 2: Preparation of7-Methoxy-8-(oxiran-2-ylmethoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine

Intermediate G was synthesized in an analogous manner Intermediate F,Step 2 substituting racemic glycidyl methanesulfonate for (R)-glycidylmethanesulfonate (0.30 g, 24%): HPLC ret. time 0.62 min.; ¹H NMR(DMSO-d₆+1 drop TFA-d) δ 2.71 (dd, J=2.5, 4.8 Hz, 1H), 2.85, (t, J=4.6Hz, 1H), 3.34-3.40 (br m, 1H), 4.30 (dd, J=6.6, 11.4 Hz, 1H), 4.10 (brt, J=9.7 Hz, 2H), 4.31 (brt, J=9.7 Hz, 2H), 4.54 (dd, J=2.3, 11.6 Hz,1H), 7.21 (d, J=9.4 Hz, 1H), 7.79 (d, J=9.1 Hz, 1H).

Intermediate H Preparation of7-methoxy-8-[(2S)-oxiran-2-ylmethoxy]-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine

Step 1: Preparation of (S)-Glycidyl Methanesulfonate

(S)-Glycidyl Methanesulfonate was synthesized in an analogous manner toIntermediate F, Step 1, substituting (R)-(+)-glycidol for(S)-(−)-glycidol. This was used in further transformations as a solutionof (S)-glycidyl methanesulfonate in DMF, without further purification.

Step 2: Preparation of7-methoxy-8-[(2S)-oxiran-2-ylmethoxy]-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine

Intermediate G was synthesized in an analogous manner Intermediate F,Step 2 substituting (S)-glycidyl methanesulfonate for (R)-glycidylmethanesulfonate (0.14 g, 15%): HPLC ret. time 0.62 min.; ¹H NMR(DMSO-d₆+1 drop TFA-d) δ 2.71 (dd, J=2.5, 4.8 Hz, 1H), 2.85, (t, J=4.6Hz, 1H), 3.34-3.40 (br m, 1H), 4.30 (dd, J=6.6, 11.4 Hz, 1H), 4.10 (brt, J=9.7 Hz, 2H), 4.31 (br t, J=9.7 Hz, 2H), 4.54 (dd, J=2.3, 11.6 Hz,1H), 7.21 (d, J=9.4 Hz, 1H), 7.79 (d, J=9.1 Hz, 1H).

Intermediate I Preparation ofN-[7-methoxy-8-(oxiran-2-ylmethoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide

Step 1: Preparation ofN-[8-(benzyloxy)-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide

To a suspension of8-(benzyloxy)-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine (21g, 65 mmol) and nicotinic acid (12 g, 97.7 mmol) in DMF (240 mL) wasadded diisopropylethylamine (33.7 g, 260.4 mmol) followed by PYBOP (51g, 97.7 mmol). The resulting mixture was stirred with the aid of anoverhead stirrer for 3 days at ambient temperature. The resultantprecipitate was isolated by vacuum filtration, washed repeatedly withEtOAc and dried under vacuum with slight heating to yieldN-[8-(benzyloxy)-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide(27.3 g, 98%): ¹H NMR (DMSO-d₆+2 drops TFA-d) δ: 9.32 (1H, s), 8.89 (1H,br m), 8.84 (1H, d), 7.89 (1H, br m), 7.82 (1H, d), 7.37 (1H, d), 7.27(1H, d), 7.16 (6H, m), 5.18 (2H, s), 4.36 (2H, t), 4.04 (2H, t), 3.78(3H, s); mass spectrum m/z 338 ((M+1)⁺, 6%).

Step 2: Preparation ofN-(8-hydroxy-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide

N-[8-(Benzyloxy)-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide(20 g, 45.1 mmol) was added portionwise over 1 h to a round bottom flaskcontaining TFA (400 mL) precooled with an ice bath. The reaction mixturewas heated to 60° C. and allowed to stir at this temperature for 17 h atwhich time it was cooled to room temperature. The reaction mixture wasthen concentrated under reduced pressure. The resulting residue wasdissolved in CH₂Cl₂ and hexane and concentrated under reduced pressure.The material thus obtained was dissolved in MeOH and CH₂Cl₂ (250 mL,1:1) and concentrated under reduced pressure. The resulting solids weredried overnight under vacuum with low heat to giveN-(8-hydroxy-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide(17.3 g, 66%): ¹H NMR (DMSO-d₆+2 drops TFA-d) δ: 13.41 (1H, s), 12.21(1H, br s), 9.38 (1H, s), 8.78 (1H, d), 8.53 (1H, d), 7.85 (1H, d), 7.59(1H, m), 7.17 (1H, d), 4.54 (2H, m), 4.21 (2H, m), 3.98 (3H, s); massspectrum m/z 481 ((M+1)⁺).

Step 3: Preparation ofN-[7-methoxy-8-(oxiran-2-ylmethoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide

A mixture ofN-{8-hydroxy-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}pyridine-3-carboxamide(0.85 g, 1.50 mmol) and caesium carbonate (2.93 g, 8.99 mmol, 6.0equiv.) in DMF (12.5 mL) was stirred at room temperature for 1 h, thenwas treated with racemic epichlorohydrin (0.29 mL, 3.75 mmol, 2.5equiv.), and the resulting mixture was stirred at room temperature for16 h. The resulting mixture was used in further transformations as a0.120 M solution ofN-[7-methoxy-8-(oxiran-2-ylmethoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamidein DMF.

Intermediate J Preparation ofN-{7-methoxy-8-[(2R)-oxiran-2-ylmethoxy]-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamide

A mixture ofN-{8-hydroxy-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}pyridine-3-carboxamide(Intermediate I, Step 2 (used as bis-TFA salt), 1.50 g, 2.65 mmol) andcaesium carbonate (4.32 g, 13.3 mmol, 5.0 equiv.) in DMF (37 mL) wasstirred at room temperature for 1 h, then was treated with (R)-glycidylmethanesulfonate (Intermediate F, Step 1, 21.2 mL, 0.25 M in DMF, 5.31mmol, 2.0 equiv.). The resulting mixture was stirred at room temperaturefor 16 h at 60° C., then was cooled to room temperature and concentratedunder reduced pressure. The resulting residue was separated betweenwater (50 mL) and a 4:1 CH₂Cl₂/isopropanol solution (50 mL). The organicphase was washed with a concentrated sodium bicarbonate solution, dried(anh. sodium sulfate), and concentrated under reduced pressure. Theresulting material was triturated with EtOH and dried under reducedpressure to giveN-{7-methoxy-8-[(2R)-oxiran-2-ylmethoxy]-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamide(0.72 g, 69%): HPLC ret. time 0.94 min.; ¹H NMR (DMSO-d₆+1 drop TFA-d) δ2.75 (dd, J=2.5, 5.1 Hz, 1H), 2.88 (app t, J=4.7, 1H), 3-42-3.47 (m,1H), 4.01 (s, 3H), 4.14 (dd, J=6.6, 11.6 Hz, 1H), 4.20-4.29 (m, 3H),4.52-4.59 (m, 2H), 4.68 (dd, J=2.3, 11.6 Hz, 1H), 7.47 (d, J=9.4 Hz,1H), 7.92 (dd, J=5.6, 7.8 Hz, 1H), 8.03 (d, J=9.1 Hz, 1H), 8.90 (br d,J=7.8 Hz, 1H), 8.97 (dd, J=1.5, 5.6 Hz, 1H), 9.49 (d, J=1.5 Hz, 1H);mass spectrum m/z 394 ((M+1)⁺, 11%).

EXAMPLES Comparative Example 1 From WO 2008/070150

Preparation ofN-{8-[2-hydroxy-3-(morpholin-4-yl)propoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}pyridine-3-carboxamide

Caesium carbonate (3 g, 9.37 mmol) was added to a suspension ofN-(8-hydroxy-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamidebis-trifluoroacetate (1.0 g, 1.88 mmol) in DMF (40 mL) and stirred for1.5 h before adding4-[(2-oxido-1,3,2-dioxathiolan-4-yl)methyl]morpholine hydrochloride(Intermediate C, 0.39 g, 1.88 mmol). After 3 h, the reaction mixture wastreated with another equivalent of4-[(2-oxido-1,3,2-dioxathiolan-4-yl)methyl]morpholine hydrochloride(Intermediate C, Step 2) and stirred at 60° C. overnight. The reactionmixture was concentrated under reduced pressure and the product wasextracted with a solution of 20% isopropanol/80% chloroform and washedwith a saturated solution of sodium hydrogen carbonate. The organicswere dried (magnesium sulfate) and concentrated under reduced pressure,and the resulting residue was triturated with EtOAc and filtered. Thesolid was then purified by HPLC (Gilson, 5% MeOH/95% H₂O to 50% MeOH/50%H₂O gradient, 0.1% NH₄OH) to giveN-{8-[2-hydroxy-3-(morpholin-4-yl)propoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}pyridine-3-carboxamide(160 mg, 18%): HPLC MS RT=0.19 min.; ¹H NMR (DMSO-d₆+1 drop TFA-d) δ13.40-13.38 (1H, br s), 9.45 (1H, d), 8.90 (1H, dd), 8.72 (1H, d), 8.06(1H, d), 7.77 (1H, dd), 7.51 (1H, d) 4.59 (2H, t), 4.49-4.41 (1H, br s),4.33-4.22 (4H, m), 4.06 (3H, s) 4.05-3.92 (2H, m), 3.86-3.67 (2H, m),3.51 (2H, d), 3.43-3.13 (4H, m); mass spectrum m/z 495 ((M+1)⁺).

Example 2 Preparation ofN-(8-{[(2R)-2-hydroxy-3-(morpholin-4-yl)propyl]oxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)pyridine-1-carboxamide

Step 1: Preparation of (2R)-3-(4-morpholinyl)-1,2-propanediol

A solution of (S)-glycidol (1.00 mL, 15.0 mmol) and morpholine (1.96 mL,22.5 mmol, 2.5 equiv.) in abs. ethanol was heated in a microwave for 4min. at 140 0° C., cooled to room temperature and concentrated at 70° C.under a 12 mbar vacuum to afford (2R)-3-(4-morpholinyl)-1,2-propanediol(2.47 g, 102%): ¹H NMR (CDCl₃) δ 2.37 (dd J=4.0, 12.4 Hz, 1H), 2.40-2.48(m, 2H), 2.57 (dd, J=9.6, 12.4 Hz, 1H), 2.62-2.71 (m, 2H), 3.50 (dd,J=4.2, 11.4 Hz, 1H), 3.65-3.79 (m, 5H), 3.79-3.88 (m, 1H).

Step 2: Preparation of4-[(4R)-(2-oxido-1,3,2-dioxathiolan-4-yl)methyl]morpholine hydrochloride

To a solution of (2R)-3-(4-morpholinyl)-1,2-propanediol (0.447 g, 2.77mmol) in CH₂Cl₂ (7.5 mL) was cooled to 0° C. and added thionyl chloride(0.41 mL, 5.55 mmol, 2.0 equiv.) was added dropwise. The resultingsolution was heated at the reflux temperature for 1 hr, cooled to roomtemperature and concentrated under reduced pressure to give4-[(4R)-(2-oxido-1,3,2-dioxathiolan-4-yl)methyl]morpholine hydrochloride(0.70 g, 104%). This material was used in the next step without furtherpurification.

Step 3: Preparation ofN-(8-{[(2R)-2-hydroxy-3-(morpholin-4-yl)propyl]oxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)pyridine-3-carboxamide

To a solution ofN-(8-hydroxy-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamidebis-TFA salt (Intermediate I, Step 2, 0.750 g, 1.3 mmol) in DMF (50 mL)was added caesium carbonate (1.30 g, 3.9 mmol, 3.0 equiv.) and theresulting slurry was stirred at room temperature for 1.5 hr, followed bythe addition of cyclic sulfite ester (0.275 g, 1.3 mmol, 1.0 equiv).This mixture was stirred at 60° C. for 12 hr, cooled to roomtemperature, treated with additional caesium carbonate (0.86 g, 2.6mmol, 2.0 equiv.) and cyclic sulfite ester (0.275 g, 1.3 mmol, 1.0equiv.) and stirred at 60° C. for an additional 12 hr. The resultingmixture was concentrated under reduced pressure. The residue wasdissolved in a 4:1 CH₂Cl₂/isopropanol solution (100 mL), then was washedwith a saturated sodium bicarbonate solution (50 mL) and a saturatedsodium chloride solution (50 mL), dried (anh. sodium sulfate), andconcentrated under reduced pressure. The residue (1.77 g) was purifiedby preparative HPLC to giveN-(8-{[(2R)-2-hydroxy-3-(morpholin-4-yl)propyl]oxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)pyridine-3-carboxamide(0.52 g, 82%): TLC (9:1 CH₂Cl₂/MeOH+1% NH₄OH in MeOH)R_(f) 0.35;Preparative HPLC (condition A) ret. time 3.70 min.; ¹H NMR (DMSO-d₆+1drop TFA-d) δ 3.10-3.40 (m, 4H), 3.47 (br d, J=11.9 Hz, 2H), 3.63-3.84(m, 2H), 3.88-4.01 (m, 2H), 4.03 (s, 3H), 4.20-4.30 (m, 4H), 4.42 (br s,1H), 4.57 (app t, J=10.3 Hz, 2H), 7.50 (d, J=9.2 Hz, 1H), 7.96 (dd,J=5.0, 7.5 Hz, 1H), 8.04 (d, J=9.2 Hz, 1H), 8.94 (br d, J=7.7 Hz, 1H),8.99 (D, J=5.2 Hz, 1H), 9.50 (d, J=1.1 Hz, 1H); mass spectrum m/z 481((M+1)⁺, 11%).

Example 3 Preparation ofN-(8-{[(2S)-2-hydroxy-3-(morpholin-4-yl)propyl]oxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)pyridine-3-carboxamide

Step 1: Preparation of (2S)-3-(4-morpholinyl)-1,2-propanediol

A solution of (R)-glycidol (0.33 mL, 5.0 mmol) and morpholine (0.65 mL,7.5 mmol, 1.5 equiv.) in abs. ethanol was heated in a microwave for 4min. at 140 0° C., cooled to room temperature and concentrated at 70° C.under a 12 mBar vacuum to afford (2S)-3-(4-morpholinyl)-1,2-propanediol(0.91 g, 113%): ¹H NMR (CDCl₃) δ 2.37 (dd, J=3.9, 12.5 Hz, 1H),2.41-2.48 (m, 2H), 2.57 (dd, J=9.7, 12.5 Hz, 1H), 3.51 (dd, J=4.3, 11.4Hz, 1H), 3.66-3.79 (m, 5H), 3.81-3.87 (m, 1H).

Step 2: Preparation of4-[(4S)-(2-oxido-1,3,2-dioxathiolan-4-yl)methyl]morpholine hydrochloride

To a solution of (2S)-3-(4-morpholinyl)-1,2-propanediol (0.90 g, 5.6mmol) in CH₂Cl₂ (7.5 mL) was cooled to 0° C. and added thionyl chloride(0.81 mL, 11.1 mmol, 2.0 equiv.) was added dropwise. The resultingsolution was heated at the reflux temperature for 1 hr, cooled to roomtemperature and concentrated under reduced pressure to give4-[(4S)-(2-oxido-1,3,2-dioxathiolan-4-yl)methyl]morpholine hydrochloride(1.40 g, 103%). This material was used in the next step without furtherpurification.

Step 3: Preparation ofN-(8-{[(2S)-2-hydroxy-3-(morpholin-4-yl)propyl]oxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)pyridine-3-carboxamide

To a solution ofN-(8-hydroxy-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamidebis-TFA salt (Intermediate I, Step 2, 0.210 g, 0.37 mmol) in DMF (12 mL)was added Cs₂CO₃ (0.61 g, 1.86 mmol, 5.0 equiv.) and the resultingslurry was stirred at room temperature for 1.5 hr, followed by theaddition of cyclic sulfite ester (0.092 g, 0.45 mmol, 1.2 equiv). Thismixture was stirred at 60° C. for 12 hr, cooled to room temperature,treated with additional caesium carbonate (0.86 g, 2.6 mmol, 2.0 equiv.)and cyclic sulfite ester (0.076 g, 0.37 mmol, 1.0 equiv.) and stirred at60° C. for an additional 3.5 days. The resulting mixture wasconcentrated under reduced pressure. The residue was dissolved in a 4:1CH₂Cl₂/isopropanol solution (50 mL), then was washed with a saturatedNaHCO₃ (25 mL) and a saturated NaCl solution (25 mL), dried (anh.Na₂SO₄), and concentrated under reduced pressure. Trituration with MeOHafforded crystals that were washed with water, then MeOH, and dried at50° C. under reduced pressure. The resulting solids (0.077 g) werepurified by preparative HPLC to giveN-(8-{[(2S)-2-hydroxy-3-(morpholin-4-yl)propyl]oxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)pyridine-3-carboxamide(0.52 g, 82%): TLC (9:1 CH₂Cl₂/MeOH+1% NH₄OH in MeOH) R_(f) 0.35; HPLC(condition A) ret. time 4.29 min.; ¹H NMR (DMSO-d₆+1 drop TFA-d) δ3.09-3.41 (m, 4H), 3.48 (br d, J=11.7 Hz, 2H), 3.62-3.85 (m, 2H),3.88-4.01 (m, 2H), 4.03 (s, 3H), 4.20-4.31 (m, 4H), 4.41 (br s, 1H),4.52-4.62 (m, 2H), 7.50 (d, J=9.4 Hz, 1H), 7.95 (dd, J=5.3, 7.9 Hz, 1H),8.04 (d, J=9.2 Hz, 1H), 8.92 (br d, J=8.1 Hz, 1H), 8.98 (dd, J=1.1, 5.3Hz, 1H), 9.49 (d, J=1.5 Hz, 1H).

Example 4 Preparation ofN-[8-({(2R)-3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-2-hydroxypropyl}oxy)-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyridine-3-carboxamide

Step 1: Preparation ofN-[8-({(2R)-3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-2-hydroxypropyl}oxy)-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]amine

A solution of7-Methoxy-8-[(2R)-oxiran-2-ylmethoxy]-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine(Intermediate F, 1.50 g, 5.20 mmol) and cis-2,6-dimethylmorpholine (6.4mL, 52.0 mmol, 10 equiv.) in DMF (36 mL) was heated in two portions in amicrowave reactor for 45 min. at 140° C. The resulting combined mixtureswere concentrated under reduced pressure and purified using MPLC to giveN-[8-({(2R)-3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-2-hydroxypropyl}oxy)-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]amine(2.02 g, 96%): Preparative HPLC ret. time 4.29 min.; ¹H NMR (DMSO-d₆+1drop TFA-d) δ 1.10 (d, J=7.3 Hz, 3H), 1.14 (d, J=7.3 Hz, 3H), 2.69 (t,J=11.6 Hz, 1H), 2.76 (t, J=11.6 Hz, 1H), 3.23-3.32 (m, 2H), 3.43-3.54(m, 2H), 3.80 (s, 3H), 3.81-3.87 (m, 1H), 3.88-3.97 (m, 1H), 4.31 (appdd, J=8.6, 12.1 Hz, 2H), 4.35-4.43 (m, 1H), 7.22 (J=9.4 Hz, 1H), 7.81(d, J=9.1 Hz, 1H); mass spectrum m/z 404 ((M+1)⁺, 100%).

Step 2: Preparation ofN-[8-({(2R)-3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-2-hydroxypropyl}oxy)-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyridine-3-carboxamide

A mixture ofN-[8-({(2R)-3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-2-hydroxypropyl}oxy)-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]amine(2.02 g, 5.01 mmol) and nicotinic acid (0.80 g, 6.51 mmol, 1.3 equiv) inDMF (139 mL) was treated with PyBOP (3.39 g, 6.51 mmol, 1.3 equiv.)followed by N,N-diisopropylethylamine (3.50 mL, 20.0 mmol, 4.0 equiv.)slowly leading to a clear solution. The mixture was stirred at roomtemperature for 24 h. The resulting solids were filtered and washed withDMF, H₂O, and MeOH, then dried at 60° C. under reduced pressure to giveN-[8-({(2R)-3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-2-hydroxypropyl}oxy)-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyridine-3-carboxamide(1.64 g, 64%): TLC (9:1 CH₂Cl₂/MeOH+1% NH₄OH in MeOH) R_(f) 0.40; ¹H NMR(DMSO-d₆+1 drop TFA-d) δ 1.15 (d, J=9.5 Hz, 3H), 1.16 (d, J=9.5 Hz, 3H),2.76 (t, J=11.2 Hz, 1H), 2.83 (t, J=11.4 Hz, 1H), 3.26-3.38 (m, 2H),3.50-3.58 (m, 2H), 3.86-3.93 (m, 1H), 3.95-4.02 (m, 1H), 4.08 (s, 3H),4.26-4.33 (m, 4H), 4.50 (br s, 1H), 4.61 (app t, J=10.7 Hz, 2H), 7.54(d, J=9.1 Hz, 1H), 7.96 (dd, J=5.7, 7.6 Hz, 1H), 8.09 (d, J=9.1 Hz, 1H),8.92 (d, J=7.9 Hz, 1H), 9.01 (d, J=4.1 Hz, 1H), 9.53 (s, 1H); massspectrum m/z 507 ((M−1)⁻, 100%), 509 ((M+1)⁺, 24%).

The following examples were prepared in a manner analogous to Example 4:

Example 5rel-2-Amino-N-(8-{[(2R)-2-hydroxy-3-{[(1R)-1-phenylethyl]amino}propyl]oxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)pyrimidine-5-carboxamide

Prepared using Intermediate G in place of Intermediate F and(S)-1-phenylethylamine in place of cis-2,6-dimethylmorpholine in Step 1and 2-amino-5-pyrimidinecarboxylic acid in place of nicotinic acid inStep 2 to afford a 1:1 mixture of disatereomers (0.11 g, 56%): HPLC ret.time 0.87 min.; ¹H NMR (DMSO-d₆+1 drop TFA-d) δ 1.58 (d, J=6.8 Hz, 3H),2.65-3.05 (m, 2H), 3.73 (s, 1.5H), 3.76 (s, 1.5H), 4.13-4.25 (m, 5H),4.40-4.52 (m, 3H), 7.32-7.36 (m, 1H), 7.39-7.46 (m, 3H), 7.50-7.54 (m,2H), 7.93-7.97 (m, 1H), 8.98 (s, 2H); mass spectrum m/z 531 ((M+1)⁺,15%).

Example 62-Amino-N-(8-{[(2S)-2-hydroxy-3-{[(1S)-1-phenylethyl]amino}propyl]oxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)pyrimidine-5-carboxamide

Prepared using Intermediate H in place of Intermediate F and(S)-1-phenylethylamine in place of cis-2,6-dimethylmorpholine in Step 1and 2-amino-5-pyrimidinecarboxylic acid in place of nicotinic acid inStep 2 to afford an 85:15 mixture of disatereomers (0.11 g, 56%): HPLCret. time 1.00 min.; ¹H NMR (DMSO-d₆+1 drop TFA-d) δ 1.58 (d, J=6.8 Hz,3H), 2.81-2.99 (m, 2H), 3.73 (s, 0.4H), 3.76 (s, 2.5H), 4.13-4.22 (m,5H), 4.39-4.52 (m, 3H), 7.35 (d, J=9.4 Hz, 1H), 7.38-7.45 (m, 3H),7.50-7.53 (m, 2H), 7.93-7.97 (m, 1H), 8.98 (s, 2H); mass spectrum m/z529 ((M−1)⁻, 47%).

Example 72-Amino-N-(8-{[(2R)-2-hydroxy-3-{[(1S)-1-phenylethyl]amino}propyl]oxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)pyrimidine-5-carboxamide

Prepared using (S)-1-phenylethylamine in place ofcis-2,6-dimethylmorpholine in Step 1 and 2-amino-5-pyrimidinecarboxylicacid in place of nicotinic acid in Step 2 to afford an 15:85 mixture ofdisatereomers (0.065 g, 85%): ¹H NMR (DMSO-d₆+1 drop TFA-d) δ 1.58 (d,J=6.8 Hz, 3H), 2.65-2.73 (br m, 1H), 2.98-3.07 (m, 1H), 3.73 (s, 2.4H),3.76 (s, 0.5H), 4.13-4.26 (m, 5H), 4.40-4.53 (m, 3H), 7.33 (d, J=9.2 Hz,1H), 7.38-7.47 (m, 3H), 7.49-7.55 (m, 2H), 7.95 (d, J=9.0 Hz, 1H), 8.98(s, 2H); mass spectrum m/z 531 ((M+1)⁺, 1.9%).

Further, the compounds of formula (I) of the present invention can beconverted to any salt as described herein, by any method which is knownto the person skilled in the art. Similarly, any salt of a compound offormula (I) of the present invention can be converted into the freecompound, by any method which is known to the person skilled in the art.

Pharmaceutical Compositions of the Compounds of the Invention

This invention also relates to pharmaceutical compositions containingone or more compounds of the present invention. These compositions canbe utilised to achieve the desired pharmacological effect byadministration to a patient in need thereof. A patient, for the purposeof this invention, is a mammal, including a human, in need of treatmentfor the particular condition or disease. Therefore, the presentinvention includes pharmaceutical compositions that are comprised of apharmaceutically acceptable carrier and a pharmaceutically effectiveamount of a compound, or salt thereof, of the present invention. Apharmaceutically acceptable carrier is preferably a carrier that isrelatively non-toxic and innocuous to a patient at concentrationsconsistent with effective activity of the active ingredient so that anyside effects ascribable to the carrier do not vitiate the beneficialeffects of the active ingredient. A pharmaceutically effective amount ofcompound is preferably that amount which produces a result or exerts aninfluence on the particular condition being treated. The compounds ofthe present invention can be administered withpharmaceutically-acceptable carriers well known in the art using anyeffective conventional dosage unit forms, including immediate, slow andtimed release preparations, orally, parenterally, topically, nasally,ophthalmically, optically, sublingually, rectally, vaginally, and thelike.

For oral administration, the compounds can be formulated into solid orliquid preparations such as capsules, pills, tablets, troches, lozenges,melts, powders, solutions, suspensions, or emulsions, and may beprepared according to methods known to the art for the manufacture ofpharmaceutical compositions. The solid unit dosage forms can be acapsule that can be of the ordinary hard- or soft-shelled gelatin typecontaining, for example, surfactants, lubricants, and inert fillers suchas lactose, sucrose, calcium phosphate, and corn starch.

In another embodiment, the compounds of this invention may be tabletedwith conventional tablet bases such as lactose, sucrose and cornstarchin combination with binders such as acacia, corn starch or gelatin,disintegrating agents intended to assist the break-up and dissolution ofthe tablet following administration such as potato starch, alginic acid,corn starch, and guar gum, gum tragacanth, acacia, lubricants intendedto improve the flow of tablet granulation and to prevent the adhesion oftablet material to the surfaces of the tablet dies and punches, forexample talc, stearic acid, or magnesium, calcium or zinc stearate,dyes, coloring agents, and flavoring agents such as peppermint, oil ofwintergreen, or cherry flavoring, intended to enhance the aestheticqualities of the tablets and make them more acceptable to the patient.Suitable excipients for use in oral liquid dosage forms includedicalcium phosphate and diluents such as water and alcohols, forexample, ethanol, benzyl alcohol, and polyethylene alcohols, either withor without the addition of a pharmaceutically acceptable surfactant,suspending agent or emulsifying agent. Various other materials may bepresent as coatings or to otherwise modify the physical form of thedosage unit. For instance tablets, pills or capsules may be coated withshellac, sugar or both.

Dispersible powders and granules are suitable for the preparation of anaqueous suspension. They provide the active ingredient in admixture witha dispersing or wetting agent, a suspending agent and one or morepreservatives. Suitable dispersing or wetting agents and suspendingagents are exemplified by those already mentioned above. Additionalexcipients, for example those sweetening, flavoring and coloring agentsdescribed above, may also be present.

The pharmaceutical compositions of this invention may also be in theform of oil-in-water emulsions. The oily phase may be a vegetable oilsuch as liquid paraffin or a mixture of vegetable oils. Suitableemulsifying agents may be (1) naturally occurring gums such as gumacacia and gum tragacanth, (2) naturally occurring phosphatides such assoy bean and lecithin, (3) esters or partial esters derived form fattyacids and hexitol anhydrides, for example, sorbitan monooleate, (4)condensation products of said partial esters with ethylene oxide, forexample, polyoxyethylene sorbitan monooleate. The emulsions may alsocontain sweetening and flavoring agents.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil such as, for example, arachis oil, olive oil, sesameoil or coconut oil, or in a mineral oil such as liquid paraffin. Theoily suspensions may contain a thickening agent such as, for example,beeswax, hard paraffin, or cetyl alcohol. The suspensions may alsocontain one or more preservatives, for example, ethyl or n-propylp-hydroxybenzoate; one or more coloring agents; one or more flavoringagents; and one or more sweetening agents such as sucrose or saccharin.

Syrups and elixirs may be formulated with sweetening agents such as, forexample, glycerol, propylene glycol, sorbitol or sucrose. Suchformulations may also contain a demulcent, and preservative, such asmethyl and propyl parabens and flavoring and coloring agents.

The compounds of this invention may also be administered parenterally,that is, subcutaneously, intravenously, intraocularly, intrasynovially,intramuscularly, or interperitoneally, as injectable dosages of thecompound in preferably a physiologically acceptable diluent with apharmaceutical carrier which can be a sterile iquid or mixture of iquidssuch as water, saline, aqueous dextrose and related sugar solutions, analcohol such as ethanol, isopropanol, or hexadecyl alcohol, glycols suchas propylene glycol or polyethylene glycol, glycerol ketals such as2,2-dimethyl-1,1-dioxolane-4-methanol, ethers such as poly(ethyleneglycol) 400, an oil, a fatty acid, a fatty acid ester or, a fatty acidglyceride, or an acetylated fatty acid glyceride, with or without theaddition of a pharmaceutically acceptable surfactant such as a soap or adetergent, suspending agent such as pectin, carbomers, methycellutose,hydroxypropylmethylcelluose, or carboxymethylcellulose, or emulsifyingagent and other pharmaceutical adjuvants.

Illustrative of oils which can be used in the parenteral formulations ofthis invention are those of petroleum, animal, vegetable, or syntheticorigin, for example, peanut oil, soybean oil, sesame oil, cottonseedoil, corn oil, olive oil, petrolatum and mineral oil. Suitable fattyacids include oleic acid, stearic acid, isostearic acid and myristicacid. Suitable fatty acid esters are, for example, ethyl oleate andisopropyl myristate. Suitable soaps include fatty acid alkali metal,ammonium, and triethanolamine salts and suitable detergents includecationic detergents, for example dimethyl dialkyl ammonium halides,alkyl pyridinium halides, and alkylamine acetates; anionic detergents,for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether,and monoglyceride sulfates, and sulfosuccinates; non-ionic detergents,for example, fatty amine oxides, fatty acid alkanolamides, andpoly(oxyethylene-oxypropylene)s or ethylene oxide or propylene oxidecopolymers; and amphoteric detergents, for example,alkyl-beta-aminopropionates, and 2-alkylimidazoline quarternary ammoniumsalts, as well as mixtures.

The parenteral compositions of this invention will typically containfrom about 0.5% to about 25% by weight of the active ingredient insolution. Preservatives and buffers may also be used advantageously. Inorder to minimise or eliminate irritation at the site of injection, suchcompositions may contain a non-ionic surfactant having ahydrophile-lipophile balance (HLB) preferably of from about 12 to about17. The quantity of surfactant in such formulation preferably rangesfrom about 5% to about 15% by weight. The surfactant can be a singlecomponent having the above HLB or can be a mixture of two or morecomponents having the desired HLB.

Illustrative of surfactants used in parenteral formulations are theclass of polyethylene sorbitan fatty acid esters, for example, sorbitanmonooleate and the high molecular weight adducts of ethylene oxide witha hydrophobic base, formed by the condensation of propylene oxide withpropylene glycol.

The pharmaceutical compositions may be in the form of sterile injectableaqueous suspensions. Such suspensions may be formulated according toknown methods using suitable dispersing or wetting agents and suspendingagents such as, for example, sodium carboxymethylcelluose,methylcellulose, hydroxypropylmethyl-celluose, sodium alginate,polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing orwetting agents which may be a naturally occurring phosphatide such aslecithin, a condensation product of an alkylene oxide with a fatty acid,for example, polyoxyethylene stearate, a condensation product ofethylene oxide with a long chain aliphatic alcohol, for example,heptadeca-ethyleneoxycetanol, a condensation product of ethylene oxidewith a partial ester derived form a fatty acid and a hexitol such aspolyoxyethylene sorbitol monooleate, or a condensation product of anethylene oxide with a partial ester derived from a fatty acid and ahexitol anhydride, for example polyoxyethylene sorbitan monooleate.

The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally acceptable diluent orsolvent. Diluents and solvents that may be employed are, for example,water, Ringer's solution, isotonic sodium chloride solutions andisotonic glucose solutions. In addition, sterile fixed oils areconventionally employed as solvents or suspending media. For thispurpose, any bland, fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid can be usedin the preparation of injectables.

A composition of the invention may also be administered in the form ofsuppositories for rectal administration of the drug. These compositionscan be prepared by mixing the drug with a suitable non-irritationexcipient which is solid at ordinary temperatures but liquid at therectal temperature and will therefore melt in the rectum to release thedrug. Such materials are, for example, cocoa butter and polyethyleneglycol.

Another formulation employed in the methods of the present inventionemploys transdermal delivery devices (“patches”). Such transdermalpatches may be used to provide continuous or discontinuous infusion ofthe compounds of the present invention in controlled amounts. Theconstruction and use of transdermal patches for the delivery ofpharmaceutical agents is well known in the art (see, e.g., U.S. Pat. No.5,023,252, issued Jun. 11, 1991, incorporated herein by reference). Suchpatches may be constructed for continuous, pulsatile, or on demanddelivery of pharmaceutical agents.

Controlled release formulations for parenteral administration includeliposomal, polymeric microsphere and polymeric gel formulations that areknown in the art.

It may be desirable or necessary to introduce the pharmaceuticalcomposition to the patient via a mechanical delivery device. Theconstruction and use of mechanical delivery devices for the delivery ofpharmaceutical agents is well known in the art. Direct techniques for,for example, administering a drug directly to the brain usually involveplacement of a drug delivery catheter into the patient's ventricularsystem to bypass the blood-brain barrier. One such implantable deliverysystem, used for the transport of agents to specific anatomical regionsof the body, is described in U.S. Pat. No. 5,011,472, issued Apr. 30,1991.

The compositions of the invention can also contain other conventionalpharmaceutically acceptable compounding ingredients, generally referredto as carriers or diluents, as necessary or desired. Conventionalprocedures for preparing such compositions in appropriate dosage formscan be utilized. Such ingredients and procedures include those describedin the following references, each of which is incorporated herein byreference: Powell, M. F. et al., “Compendium of Excipients forParenteral Formulations” PDA Journal of Pharmaceutical Science ETechnology 1998, 52(5), 238-311; Strickley, R. G “ParenteralFormulations of Small Molecule Therapeutics Marketed in the UnitedStates (1999)-Part-1” PDA Journal of Pharmaceutical Science t Technology1999, 53(6), 324-349; and Nema, S. et al., “Excipients and Their Use inInjectable Products” PDA Journal of Pharmaceutical Science t Technology1997, 51(4), 166-171.

Commonly used pharmaceutical ingredients that can be used as appropriateto formulate the composition for its intended route of administrationinclude:

acidifying agents (examples include but are not limited to acetic acid,citric acid, fumaric acid, hydrochloric acid, nitric acid);

alkalinizing agents (examples include but are not limited to ammoniasolution, ammonium carbonate, diethanolamine, monoethanolamine,potassium hydroxide, sodium borate, sodium carbonate, sodium hydroxide,triethanolamine, trolamine);

adsorbents (examples include but are not limited to powdered celluloseand activated charcoal);

aerosol propellants (examples include but are not limited to carbondioxide, CCl₂F₂, F₂ClC—CClF₂ and CClF₃)

air displacement agents (examples include but are not limited tonitrogen and argon);

antifungal preservatives (examples include but are not limited tobenzoic acid, butylparaben, ethylparaben, methylparaben, propylparaben,sodium benzoate);

antimicrobial preservatives (examples include but are not limited tobenzalkonium chloride, benzethonium chloride, benzyl alcohol,cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol,phenylmercuric nitrate and thimerosal);

antioxidants (examples include but are not limited to ascorbic acid,ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene,hypophosphorus acid, monothioglycerol, propyl gallate, sodium ascorbate,sodium bisulfite, sodium formaldehyde sulfoxylate, sodiummetabisulfite);

binding materials (examples include but are not limited to blockpolymers, natural and synthetic rubber, polyacrylates, polyurethanes,silicones, polysiloxanes and styrene-butadiene copolymers);

buffering agents (examples include but are not limited to potassiummetaphosphate, dipotassium phosphate, sodium acetate, sodium citrateanhydrous and sodium citrate dihydrate)

carrying agents (examples include but are not limited to acacia syrup,aromatic syrup, aromatic elixir, cherry syrup, cocoa syrup, orangesyrup, syrup, corn oil, mineral oil, peanut oil, sesame oil,bacteriostatic sodium chloride injection and bacteriostatic water forinjection)

chelating agents (examples include but are not limited to edetatedisodium and edetic acid)

colorants (examples include but are not limited to FD&C Red No. 3, FD&CRed No. 20, FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No. 5, D&COrange No. 5, D&C Red No. 8, caramel and ferric oxide red);

clarifying agents (examples include but are not limited to bentonite)

emulsifying agents (examples include but are not limited to acacia,cetomacrogol, cetyl alcohol, glyceryl monostearate, lecithin, sorbitanmonooleate, polyoxyethylene 50 monostearate);

encapsulating agents (examples include but are not limited to gelatinand cellulose acetate phthalate)

flavorants (examples include but are not limited to anise oil, cinnamonoil, cocoa, menthol, orange oil, peppermint oil and vanillin);

humectants (examples include but are not limited to glycerol, propyleneglycol and sorbitol);

levigating agents (examples include but are not limited to mineral oiland glycerin);

oils (examples include but are not limited to arachis oil, mineral oil,olive oil, peanut oil, sesame oil and vegetable oil);

ointment bases (examples include but are not limited to lanolin,hydrophilic ointment, polyethylene glycol ointment, petrolatum,hydrophilic petrolatum, white ointment, yellow ointment, and rose waterointment);

penetration enhancers (transdermal delivery) (examples include but arenot limited to monohydroxy or polyhydroxy alcohols, mono- or polyvalentalcohols, saturated or unsaturated fatty alcohols, saturated orunsaturated fatty esters, saturated or unsaturated dicarboxylic acids,essential oils, phosphatidyl derivatives, cephalin, terpenes, amides,ethers, ketones and ureas)

plasticizers (examples include but are not limited to diethyl phthalateand glycerol);

solvents (examples include but are not limited to ethanol, corn oil,cottonseed oil, glycerol, isopropanol, mineral oil, oleic acid, peanutoil, purified water, water for injection, sterile water for injectionand sterile water for irrigation);

stiffening agents (examples include but are not limited to cetylalcohol, cetyl esters wax, microcrystalline wax, paraffin, stearylalcohol, white wax and yellow wax);

suppository bases (examples include but are not limited to cocoa butterand polyethylene glycols (mixtures));

surfactants (examples include but are not Limited to benzalkoniumchloride, nonoxynol 10, oxtoxynol 9, polysorbate 80, sodium laurylsulfate and sorbitan mono-palmitate);

suspending agents (examples include but are not limited to agar,bentonite, carbomers, carboxymethylcellulose sodium, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose,kaolin, methylcellulose, tragacanth and veegum);

sweetening agents (examples include but are not limited to aspartame,dextrose, glycerol, mannitol, propylene glycol, saccharin sodium,sorbitol and sucrose);

tablet anti-adherents (examples include but are not limited to magnesiumstearate and talc);

tablet binders (examples include but are not limited to acacia, alginicacid, carboxymethylcellulose sodium, compressible sugar, ethylcellulose,gelatin, liquid glucose, methylcellulose, non-crosslinked polyvinylpyrrolidone, and pregelatinized starch);

tablet and capsule diluents (examples include but are not limited todibasic calcium phosphate, kaolin, lactose, mannitol, microcrystallinecellulose, powdered cellulose, precipitated calcium carbonate, sodiumcarbonate, sodium phosphate, sorbitol and starch);

tablet coating agents (examples include but are not limited to liquidglucose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, methylcellulose, ethylcellulose, cellulose acetatephthalate and shellac);

tablet direct compression excipients (examples include but are notlimited to dibasic calcium phosphate);

tablet disintegrants (examples include but are not limited to alginicacid, carboxymethylcellulose calcium, microcrystalline cellulose,polacrillin potassium, cross-linked polyvinylpyrrolidone, sodiumalginate, sodium starch glycollate and starch);

tablet glidants (examples include but are not limited to colloidalsilica, corn starch and talc);

tablet lubricants (examples include but are not limited to calciumstearate, magnesium stearate, mineral oil, stearic acid and zincstearate);

tablet/capsule opaquants (examples include but are not limited totitanium dioxide);

tablet polishing agents (examples include but are not limited to carnubawax and white wax);

thickening agents (examples include but are not limited to beeswax,cetyl alcohol and paraffin);

tonicity agents (examples include but are not limited to dextrose andsodium chloride);

viscosity increasing agents (examples include but are not Limited toalginic acid, bentonite, carbomers, carboxymethylcellulose sodium,methylcellulose, polyvinyl pyrrolidone, sodium alginate and tragacanth);and

wetting agents (examples include but are not limited toheptadecaethylene oxycetanol, lecithins, sorbitol monooleate,polyoxyethylene sorbitol monooleate, and polyoxyethylene stearate).

Pharmaceutical compositions according to the present invention can beillustrated as follows:

Sterile IV Solution:

A 5 mg/mL solution of the desired compound of this invention can be madeusing sterile, injectable water, and the pH is adjusted if necessary.The solution is diluted for administration to 1-2 mg/mL with sterile 5%dextrose and is administered as an IV infusion over about 60 minutes.

Lyophilised Powder for IV Administration:

A sterile preparation can be prepared with (i) 100-1000 mg of thedesired compound of this invention as a lyophilised powder, (ii) 32-327mg/mL sodium citrate, and (iii) 300-3000 mg Dextran 40. The formulationis reconstituted with sterile, injectable saline or dextrose 5% to aconcentration of 10 to 20 mg/mL, which is further diluted with saline ordextrose 5% to 0.2-0.4 mg/mL, and is administered either IV bolus or byIV infusion over 15-60 minutes.

Intramuscular Suspension:

The following solution or suspension can be prepared, for intramuscularinjection:

50 mg/mL of the desired, water-insoluble compound of this invention

5 mg/mL sodium carboxymethylcellulose

4 mg/mL TWEEN 80

9 mg/mL sodium chloride

9 mg/mL benzyl alcohol

Hard Shell Capsules:

A large number of unit capsules are prepared by filling standardtwo-piece hard galantine capsules each with 100 mg of powdered activeingredient, 150 mg of lactose, 50 mg of cellulose and 6 mg of magnesiumstearate.

Soft Gelatin Capsules:

A mixture of active ingredient in a digestible oil such as soybean oil,cottonseed oil or olive oil is prepared and injected by means of apositive displacement pump into molten gelatin to form soft gelatincapsules containing 100 mg of the active ingredient. The capsules arewashed and dried. The active ingredient can be dissolved in a mixture ofpolyethylene glycol, glycerin and sorbitol to prepare a water misciblemedicine mix.

Tablets:

A large number of tablets are prepared by conventional procedures sothat the dosage unit is 100 mg of active ingredient, 0.2 mg. ofcolloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg ofmicrocrystalline cellulose, 11 mg. of starch, and 98.8 mg of Lactose.Appropriate aqueous and non-aqueous coatings may be applied to increasepalatability, improve elegance and stability or delay absorption.

Immediate Release Tablets/Capsules:

These are solid oral dosage forms made by conventional and novelprocesses. These units are taken orally without water for immediatedissolution and delivery of the medication. The active ingredient ismixed in a liquid containing ingredient such as sugar, gelatin, pectinand sweeteners. These liquids are solidified into solid tablets orcaplets by freeze drying and solid state extraction techniques. The drugcompounds may be compressed with viscoelastic and thermoelastic sugarsand polymers or effervescent components to produce porous matricesintended for immediate release, without the need of water.

Combination Therapies

The compounds of this invention can be administered as the solepharmaceutical agent or in combination with one or more otherpharmaceutical agents where the combination causes no unacceptableadverse effects. The present invention relates also to suchcombinations. For example, the compounds of this invention can becombined with known anti-hyper-proliferative or other indication agents,and the like, as well as with admixtures and combinations thereof. Otherindication agents include, but are not limited to, anti-angiogenicagents, mitotic inhibitors, alkylating agents, anti-metabolites,DNA-intercalating antibiotics, growth factor inhibitors, cell cycleinhibitors, enzyme inhibitors, toposisomerase inhibitors, biologicalresponse modifiers, or anti-hormones.

The additional pharmaceutical agent can be aldesleukin, alendronic acid,alfaferone, alitretinoin, allopurinol, aloprim, aloxi, altretamine,aminoglutethimide, amifostine, amrubicin, amsacrine, anastrozole,anzmet, aranesp, arglabin, arsenic trioxide, aromasin, 5-azacytidine,azathioprine, BAY 80-6946, BCG or tice BCG, bestatin, betamethasoneacetate, betamethasone sodium phosphate, bexarotene, bleomycin sulfate,broxuridine, bortezomib, busulfan, calcitonin, campath, capecitabine,carboplatin, casodex, cefesone, celmoleukin, cerubidine, chlorambucil,cisplatin, cladribine, cladribine, clodronic acid, cyclophosphamide,cytarabine, dacarbazine, dactinomycin, DaunoXome, decadron, decadronphosphate, delestrogen, denileukin diftitox, depo-medrol, deslorelin,dexrazoxane, diethylstilbestrol, diflucan, docetaxel, doxifluridine,doxorubicin, dronabinol, DW-166HC, eligard, elitek, ellence, emend,epirubicin, epoetin alfa, epogen, eptaplatin, ergamisol, estrace,estradiol, estramustine phosphate sodium, ethinyl estradiol, ethyol,etidronic acid, etopophos, etoposide, fadrozole, farston, filgrastim,finasteride, fligrastim, floxuridine, fluconazole, fludarabine,5-fluorodeoxyuridine monophosphate, 5-fluorouracil (5-FU),fluoxymesterone, flutamide, formestane, fosteabine, fotemustine,fulvestrant, gammagard, gemcitabine, gemtuzumab, gleevec, gliadel,goserelin, granisetron HCL, histrelin, hycamtin, hydrocortone,eyrthro-hydroxynonyladenine, hydroxyurea, ibritumomab tiuxetan,idarubicin, ifosfamide, interferon alpha, interferon-alpha 2, interferonalfa-2A, interferon alfa-2B, interferon alfa-n1, interferon alfa-n3,interferon beta, interferon gamma-1a, interleukin-2, intron A, iressa,irinotecan, kytril, lentinan sulfate, letrozole, leucovorin, leuprolide,leuprolide acetate, levamisole, levofolinic acid calcium salt,levothroid, levoxyl, lomustine, lonidamine, marinol, mechlorethamine,mecobalamin, medroxyprogesterone acetate, megestrol acetate, melphalan,menest, 6-mercaptopurine, Mesna, methotrexate, metvix, miltefosine,minocycline, mitomycin C, mitotane, mitoxantrone, Modrenal, Myocet,nedaplatin, neulasta, neumega, neupogen, nilutamide, nolvadex,NSC-631570, OCT-43, octreotide, ondansetron HCl, orapred, oxaliplatin,paclitaxel, pediapred, pegaspargase, Pegasys, pentostatin, picibanil,pilocarpine HCl, pirarubicin, plicamycin, porfimer sodium,prednimustine, prednisolone, prednisone, premarin, procarbazine,procrit, raltitrexed, RDEA 119, rebif, rhenium-186 etidronate,rituximab, roferon-A, romurtide, salagen, sandostatin, sargramostim,semustine, sizofuran, sobuzoxane, solu-medrol, sparfosic acid, stem-celltherapy, streptozocin, strontium-89 chloride, synthroid, tamoxifen,tamsulosin, tasonermin, tastolactone, taxotere, teceleukin,temozolomide, teniposide, testosterone propionate, testred, thioguanine,thiotepa, thyrotropin, tiludronic acid, topotecan, toremifene,tositumomab, trastuzumab, treosulfan, tretinoin, trexall,trimethylmelamine, trimetrexate, triptorelin acetate, triptorelinpamoate, UFT, uridine, valrubicin, vesnarinone, vinblastine,vincristine, vindesine, vinorelbine, virulizin, zinecard, zinostatinstimalamer, zofran, ABI-007, acolbifene, actimmune, affinitak,aminopterin, arzoxifene, asoprisnil, atamestane, atrasentan, sorafenib,avastin, CCI-779, CDC-501, celebrex, cetuximab, crisnatol, cyproteroneacetate, decitabine, DN-101, doxorubicin-MTC, dSLIM, dutasteride,edotecarin, eflornithine, exatecan, fenretinide, histaminedihydrochloride, histrelin hydrogel implant, holmium-166 DOTMP,ibandronic acid, interferon gamma, intron-PEG, ixabepilone, keyholelimpet hemocyanin, L-651582, lanreotide, lasofoxifene, libra,lonafarnib, miproxifene, minodronate, MS-209, liposomal MTP-PE, MX-6,nafarelin, nemorubicin, neovastat, nolatrexed, oblimersen, onco-TCS,osidem, paclitaxel polyglutamate, pamidronate disodium, PN-401, QS-21,quazepam, R-1549, raloxifene, ranpirnase, 13-cis-retinoic acid,satraplatin, seocalcitol, T-138067, tarceva, taxoprexin, thymosin alpha1, tiazofurine, tipifarnib, tirapazamine, TLK-286, toremifene,TransMID-107R, valspodar, vapreotide, vatalanib, verteporfin,vinflunine, Z-100, zotedronic acid or combinations thereof.

In an embodiment of the present invention, a compound of general formula(I) as defined herein can optionally be administered in combination withone or more of the following: 131I-chTNT, abarelix, abiraterone,aclarubicin, aldesleukin, alemtuzumab, alitretinoin, altretamine,aminoglutethimide, amrubicin, amsacrine, anastrozole, arglabin, arsenictrioxide, asparaginase, azacitidine, basiliximab, BAY 80-6946, BAY1000394, BAY 86-9766 (RDEA 119), belotecan, bendamustine, bevacizumab,bexarotene, bicalutamide, bisantrene, bleomycin, bortezomib, buserelin,busulfan, cabazitaxel, calcium folinate, calcium levofolinate,capecitabine, carboplatin, carmofur, carmustine, catumaxomab, celecoxib,celmoleukin, cetuximab, chlorambucil, chlormadinone, chlormethine,cisplatin, cladribine, clodronic acid, clofarabine, crisantaspase,cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin,darbepoetin alfa, dasatinib, daunorubicin, decitabine, degarelix,denileukin diftitox, denosumab, deslorelin, dibrospidium chloride,docetaxel, doxifluridine, doxorubicin, doxorubicin+estrone, eculizumab,edrecolomab, elliptinium acetate, eltrombopag, endostatin, enocitabine,epirubicin, epitiostanol, epoetin alfa, epoetin beta, eptaplatin,eribulin, erlotinib, estradiol, estramustine, etoposide, everolimus,exemestane, fadrozole, filgrastim, fludarabine, fluorouracil, flutamide,formestane, fotemustine, fulvestrant, gallium nitrate, ganirelix,gefitinib, gemcitabine, gemtuzumab, glutoxim, goserelin, histaminedihydrochloride, histrelin, hydroxycarbamide, I-125 seeds, ibandronicacid, ibritumomab tiuxetan, idarubicin, ifosfamide, imatinib, imiquimod,improsulfan, interferon alfa, interferon beta, interferon gamma,ipilimumab, irinotecan, ixabepilone, lanreotide, lapatinib,lenalidomide, lenograstim, lentinan, letrozole, leuprorelin, levamisole,lisuride, lobaplatin, lomustine, lonidamine, masoprocol,medroxyprogesterone, megestrol, melphalan, mepitiostane, mercaptopurine,methotrexate, methoxsalen, Methyl aminolevulinate, methyltestosterone,mifamurtide, miltefosine, miriplatin, mitobronitol, mitoguazone,mitolactol, mitomycin, mitotane, mitoxantrone, nedaplatin, nelarabine,nilotinib, nilutamide, nimotuzumab, nimustine, nitracrine, ofatumumab,omeprazole, oprelvekin, oxaliplatin, p53 gene therapy, paclitaxel,palifermin, palladium-103 seed, pamidronic acid, panitumumab, pazopanib,pegaspargase, PEG-epoetin beta (methoxy PEG-epoetin beta),pegfilgrastim, peginterferon alfa-2b, pemetrexed, pentazocine,pentostatin, peplomycin, perfosfamide, picibanil, pirarubicin,plerixafor, plicamycin, poliglusam, polyestradiol phosphate,polysaccharide-K, porfimer sodium, pralatrexate, prednimustine,procarbazine, quinagolide, raloxifene, raltitrexed, ranimustine,razoxane, regorafenib, risedronic acid, rituximab, romidepsin,romiplostim, sargramostim, sipuleucel-T, sizofuran, sobuzoxane, sodiumglycididazole, sorafenib, streptozocin, sunitinib, talaporfin,tamibarotene, tamoxifen, tasonermin, teceleukin, tegafur,tegafur+gimeracil+oteracil, temoporfin, temozolomide, temsirolimus,teniposide, testosterone, tetrofosmin, thalidomide, thiotepa,thymalfasin, tioguanine, tocilizumab, topotecan, toremifene,tositumomab, trabectedin, trastuzumab, treosulfan, tretinoin,trilostane, triptorelin, trofosfamide, tryptophan, ubenimex, valrubicin,vandetanib, vapreotide, vemurafenib, vinblastine, vincristine,vindesine, vinflunine, vinorelbine, vorinostat, vorozole, yttrium-90glass microspheres, zinostatin, zinostatin stimalamer, zoledronic acid,zorubicin.

In an embodiment of the present invention, a compound of general formula(I) as defined herein can optionally be administered in combination withone or more of the following: 131I-chTNT, abarelix, abiraterone,aclarubicin, aldesleukin, alemtuzumab, alitretinoin, altretamine,aminoglutethimide, amrubicin, amsacrine, anastrozole, arglabin, arsenictrioxide, asparaginase, azacitidine, basiliximab, BAY 80-6946, BAY1000394, BAY 86-9766 (RDEA 119), belotecan, bendamustine, bevacizumab,bexarotene, bicalutamide, bisantrene, bleomycin, bortezomib, buserelin,busulfan, cabazitaxel, calcium folinate, calcium levofolinate,capecitabine, carboplatin, carmofur, carmustine, catumaxomab, celecoxib,celmoleukin, cetuximab, chlorambucil, chlormadinone, chlormethine,cisplatin, cladribine, clodronic acid, clofarabine, crisantaspase,cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin,darbepoetin alfa, dasatinib, daunorubicin, decitabine, degarelix,denileukin diftitox, denosumab, deslorelin, dibrospidium chloride,docetaxel, doxifluridine, doxorubicin, doxorubicin+estrone, eculizumab,edrecolomab, elliptinium acetate, eltrombopag, endostatin, enocitabine,epirubicin, epitiostanol, epoetin alfa, epoetin beta, eptaplatin,eribulin, erlotinib, estradiol, estramustine, etoposide, everolimus,exemestane, fadrozole, filgrastim, fludarabine, fluorouracil, flutamide,formestane, fotemustine, fulvestrant, gallium nitrate, ganirelix,gefitinib, gemcitabine, gemtuzumab, glutoxim, goserelin, histaminedihydrochloride, histrelin, hydroxycarbamide, I-125 seeds, ibandronicacid, ibritumomab tiuxetan, idarubicin, ifosfamide, imatinib, imiquimod,improsulfan, interferon alfa, interferon beta, interferon gamma,ipilimumab, irinotecan, ixabepilone, lanreotide, lapatinib,lenalidomide, lenograstim, lentinan, letrozole, leuprorelin, levamisole,lisuride, lobaplatin, lomustine, lonidamine, masoprocol,medroxyprogesterone, megestrol, melphalan, mepitiostane, mercaptopurine,methotrexate, methoxsalen, Methyl aminolevulinate, methyltestosterone,mifamurtide, miltefosine, miriplatin, mitobronitol, mitoguazone,mitolactol, mitomycin, mitotane, mitoxantrone, nedaplatin, nelarabine,nilotinib, nilutamide, nimotuzumab, nimustine, nitracrine, ofatumumab,omeprazole, oprelvekin, oxaliplatin, p53 gene therapy, paclitaxel,palifermin, palladium-103 seed, pamidronic acid, panitumumab, pazopanib,pegaspargase, PEG-epoetin beta (methoxy PEG-epoetin beta),pegfilgrastim, o0 peginterferon alfa-2b, pemetrexed, pentazocine,pentostatin, peplomycin, perfosfamide, picibanit, pirarubicin,plerixafor, plicamycin, poliglusam, polyestradiol phosphate,polysaccharide-K, porfimer sodium, pralatrexate, prednimustine,procarbazine, quinagolide, raloxifene, raltitrexed, ranimustine,razoxane, regorafenib, risedronic acid, rituximab, romidepsin,romiplostim, sargramostim, sipuleucel-T, sizofuran, sobuzoxane, sodiumglycididazole, sorafenib, streptozocin, sunitinib, talaporfin,tamibarotene, tamoxifen, tasonermin, teceleukin, tegafur,tegafur+gimeracil+oteracil, temoporfin, temozolomide, temsirolimus,teniposide, testosterone, tetrofosmin, thalidomide, thiotepa,thymalfasin, tioguanine, tocilizumab, topotecan, toremifene,tositumomab, trabectedin, trastuzumab, treosulfan, tretinoin,trilostane, triptorelin, trofosfamide, tryptophan, ubenimex, valrubicin,vandetanib, vapreotide, vemurafenib, vinblastine, vincristine,vindesine, vinflunine, vinorelbine, vorinostat, vorozole, yttrium-90glass microspheres, zinostatin, zinostatin stimalamer, zoledronic acid,zorubicin.

Optional anti-hyper-proliferative agents which can be added to thecomposition include but are not limited to compounds listed on thecancer chemotherapy drug regimens in the 11^(th) Edition of the MerckIndex, (1996), which is hereby incorporated by reference, such asasparaginase, bleomycin, carboplatin, carmustine, chlorambucil,cisplatin, colaspase, cyclophosphamide, cytarabine, dacarbazine,dactinomycin, daunorubicin, doxorubicin (adriamycine), epirubicin,etoposide, 5-fluorouracil, hexamethylmelamine, hydroxyurea, ifosfamide,irinotecan, leucovorin, lomustine, mechlorethamine, 6-mercaptopurine,mesna, methotrexate, mitomycin C, mitoxantrone, prednisolone,prednisone, procarbazine, raloxifen, streptozocin, tamoxifen,thioguanine, topotecan, vinblastine, vincristine, and vindesine.

Other anti-hyper-proliferative agents suitable for use with thecomposition of the invention include but are not limited to thosecompounds acknowledged to be used in the treatment of neoplasticdiseases in Goodman and Gilman's The Pharmacological Basis ofTherapeutics (Ninth Edition), editor Molinoff et al., publ. byMcGraw-Hill, pages 1225-1287, (1996), which is hereby incorporated byreference, such as aminoglutethimide, L-asparaginase, azathioprine,5-azacytidine cladribine, busulfan, diethylstilbestrol,2′,2′-difluorodeoxycytidine, docetaxel, erythrohydroxynonyl adenine,ethinyl estradiol, 5-fluorodeoxyuridine, 5-fluorodeoxyuridinemono-phosphate, fludarabine phosphate, fluoxymesterone, flutamide,hydroxyprogesterone caproate, idarubicin, interferon,medroxyprogesterone acetate, megestrol acetate, melphalan, mitotane,paclitaxel, pentostatin, N-phosphonoacetyl-L-aspartate (PALA),plicamycin, semustine, teniposide, testosterone propionate, thiotepa,trimethyl-melamine, uridine, and vinorelbine.

Other anti-hyper-proliferative agents suitable for use with thecomposition of the invention include but are not limited to otheranti-cancer agents such as epothilone and its derivatives, irinotecan,raloxifen and topotecan.

The compounds of the invention may also be administered in combinationwith protein therapeutics. Such protein therapeutics suitable for thetreatment of cancer or other angiogenic disorders and for use with thecompositions of the invention include, but are not limited to, aninterferon (e.g., interferon .alpha., .beta., or .gamma.) supraagonisticmonoclonal antibodies, Tuebingen, TRP-1 protein vaccine, Colostrinin,anti-FAP antibody, YH-16, gemtuzumab, infliximab, cetuximab,trastuzumab, denileukin diftitox, rituximab, thymosin alpha 1,bevacizumab, mecasermin, mecasermin rinfabate, oprelvekin, natalizumab,rhMBL, MFE-CP1+ZD-2767-P, ABT-828, ErbB2-specific immunotoxin, SGN-35,MT-103, rinfabate, AS-1402, B43-genistein, L-19 basedradioimmunotherapeutics, AC-9301, NY-ESO-1 vaccine, IMC-1C11, CT-322,rhCC10, r(m)CRP, MORAb-009, aviscumine, MDX-1307, Her-2 vaccine,APC-8024, NGR-hTNF, rhH1.3, IGN-311, Endostatin, volociximab, PRO-1762,lexatumumab, SGN-40, pertuzumab, EMD-273063, L19-IL-2 fusion protein,PRX-321, CNTO-328, MDX-214, tigapotide, CAT-3888, labetuzumab,alpha-particle-emitting radioisotope-linked lintuzumab, EM-1421,HyperAcute vaccine, tucotuzumab celmoleukin, galiximab, HPV-16-E7,Javelin—prostate cancer, Javelin—melanoma, NY-ESO-1 vaccine, EGFvaccine, CYT-004-MelQbG10, WT1 peptide, oregovomab, ofatumumab,zalutumumab, cintredekin besudotox, WX-G250, Albuferon, aflibercept,denosumab, vaccine, CTP-37, efungumab, or 131I-chTNT-1/B. Monoclonalantibodies useful as the protein therapeutic include, but are notlimited to, muromonab-CD3, abciximab, edrecolomab, daclizumab,gentuzumab, alemtuzumab, ibritumomab, cetuximab, bevicizumab,efalizumab, adalimumab, omalizumab, muromomab-CD3, rituximab,daclizumab, trastuzumab, palivizumab, basiliximab, and infliximab.

A compound of general formula (I) as defined herein can optionally beadministered in combination with one or more of the following: ARRY-162,ARRY-300, ARRY-704, AS-703026, AZD-5363, AZD-8055, BEZ-235, BGT-226,BKM-120, BYL-719, CAL-101, CC-223, CH-5132799, deforolimus, E-6201,enzastaurin, GDC-0032, GDC-0068, GDC-0623, GDC-0941, GDC-0973, GDC-0980,GSK-2110183, GSK-2126458, GSK-2141795, MK-2206, novolimus, OSI-027,perifosine, PF-04691502, PF-05212384, PX-866, rapamycin, RG-7167,RO-4987655, RO-5126766, selumetinib, TAK-733, trametinib, triciribine,UCN-01, WX-554, XL-147, XL-765, zotarolimus, ZSTK-474

Generally, the use of cytotoxic and/or cytostatic agents in combinationwith a compound or composition of the present invention will serve to:

(1) yield better efficacy in reducing the growth of a tumor or eveneliminate the tumor as compared to administration of either agent alone,

(2) provide for the administration of lesser amounts of the administeredchemo-therapeutic agents,

(3) provide for a chemotherapeutic treatment that is well tolerated inthe patient with fewer deleterious pharmacological complications thanobserved with single agent chemotherapies and certain other combinedtherapies,

(4) provide for treating a broader spectrum of different cancer types inmammals, especially humans,

(5) provide for a higher response rate among treated patients,

(6) provide for a longer survival time among treated patients comparedto standard chemotherapy treatments,

(7) provide a longer time for tumor progression, and/or

(8) yield efficacy and tolerability results at least as good as those ofthe agents used alone, compared to known instances where other canceragent combinations produce antagonistic effects.

Methods of Sensitizing Cells to Radiation

In a distinct embodiment of the present invention, a compound of thepresent invention may be used to sensitize a cell to radiation. That is,treatment of a cell with a compound of the present invention prior toradiation treatment of the cell renders the cell more susceptible to DNAdamage and cell death than the cell would be in the absence of anytreatment with a compound of the invention. In one aspect, the cell istreated with at least one compound of the invention.

Thus, the present invention also provides a method of killing a cell,wherein a cell is administered one or more compounds of the invention incombination with conventional radiation therapy.

The present invention also provides a method of rendering a cell moresusceptible to cell death, wherein the cell is treated one or morecompounds of the invention prior to the treatment of the cell to causeor induce cell death. In one aspect, after the cell is treated with oneor more compounds of the invention, the cell is treated with at leastone compound, or at least one method, or a combination thereof, in orderto cause DNA damage for the purpose of inhibiting the function of thenormal cell or killing the cell.

In one embodiment, a cell is killed by treating the cell with at leastone DNA damaging agent. That is, after treating a cell with one or morecompounds of the invention to sensitize the cell to cell death, the cellis treated with at least one DNA damaging agent to kill the cell. DNAdamaging agents useful in the present invention include, but are notLimited to, chemotherapeutic agents (e.g., cisplatinum), ionizingradiation (X-rays, ultraviolet radiation), carcinogenic agents, andmutagenic agents.

In another embodiment, a cell is killed by treating the cell with atleast one method to cause or induce DNA damage. Such methods include,but are not limited to, activation of a cell signalling pathway thatresults in DNA damage when the pathway is activated, inhibiting of acell signalling pathway that results in DNA damage when the pathway isinhibited, and inducing a biochemical change in a cell, wherein thechange results in DNA damage. By way of a non-limiting example, a DNArepair pathway in a cell can be inhibited, thereby preventing the repairof DNA damage and resulting in an abnormal accumulation of DNA damage ina cell.

In one aspect of the invention, a compound of the invention isadministered to a cell prior to the radiation or other induction of DNAdamage in the cell. In another aspect of the invention, a compound ofthe invention is administered to a cell concomitantly with the radiationor other induction of DNA damage in the cell. In yet another aspect ofthe invention, a compound of the invention is administered to a cellimmediately after radiation or other induction of DNA damage in the cellhas begun.

In another aspect, the cell is in vitro. In another embodiment, the cellis in vivo.

As mentioned supra, the compounds of the present invention havesurprisingly been found to effectively inhibit allo-MEK and maytherefore be used for the treatment or prophylaxis of diseases ofuncontrolled cell growth, proliferation and/or survival, inappropriatecellular immune responses, or inappropriate cellular inflammatoryresponses, or diseases which are accompanied with uncontrolled cellgrowth, proliferation and/or survival, inappropriate cellular immuneresponses, or inappropriate cellular inflammatory responses,particularly in which the uncontrolled cell growth, proliferation and/orsurvival, inappropriate cellular immune responses, or inappropriatecellular inflammatory responses is mediated by allo-MEK, such as, forexample, haematological tumours, solid tumours, and/or metastasesthereof, e.g. Leukaemias and myelodysplastic syndrome, malignantlymphomas, head and neck tumours including brain tumours and brainmetastases, tumours of the thorax including non-small cell and smallcell Lung tumours, gastrointestinal tumours, endocrine tumours, mammaryand other gynaecological tumours, urological tumours including renal,bladder and prostate tumours, skin tumours, and sarcomas, and/ormetastases thereof.

In accordance with another aspect therefore, the present inventioncovers a compound of general formula (I), or a stereoisomer, a tautomer,an N-oxide, a hydrate, a solvate, or a salt thereof, particularly apharmaceutically acceptable salt thereof, or a mixture of same, asdescribed and defined herein, for use in the treatment or prophylaxis ofa disease, as mentioned supra.

Another particular aspect of the present invention is therefore the useof a compound of general formula (I) described supra for manufacturing apharmaceutical composition for the treatment or prophylaxis of adisease.

The diseases referred to in the two preceding paragraphs are diseases ofuncontrolled cell growth, proliferation and/or survival, inappropriatecellular immune responses, or inappropriate cellular inflammatoryresponses, or diseases which are accompanied with uncontrolled cellgrowth, proliferation and/or survival, inappropriate cellular immuneresponses, or inappropriate cellular inflammatory responses,particularly in which the uncontrolled cell growth, proliferation and/orsurvival, inappropriate cellular immune responses, or inappropriatecellular inflammatory responses is mediated by Mps-1, such as, forexample, haematological tumours, solid tumours, and/or metastasesthereof, e.g. Leukaemias and myelodysplastic syndrome, malignantlymphomas, head and neck tumours including brain tumours and brainmetastases, tumours of the thorax including non-small cell and smallcell lung tumours, gastrointestinal tumours, endocrine tumours, mammaryand other gynaecological tumours, urological tumours including renal,bladder and prostate tumours, skin tumours, and sarcomas, and/ormetastases thereof.

The term “inappropriate” within the context of the present invention, inparticular in the context of “inappropriate cellular immune responses,or inappropriate cellular inflammatory responses”, as used herein, is tobe understood as preferably meaning a response which is less than, orgreater than normal, and which is associated with, responsible for, orresults in, the pathology of said diseases.

Preferably, the use is in the treatment or prophylaxis of diseases,wherein the diseases are haemotological tumours, solid tumours and/ormetastases thereof.

Method of Treating Hyper-Proliferative Disorders

The present invention relates to a method for using the compounds of thepresent invention and compositions thereof, to treat mammalianhyper-proliferative disorders. Compounds can be utilized to inhibit,block, reduce, decrease, etc., cell proliferation and/or cell division,and/or produce apoptosis. This method comprises administering to amammal in need thereof, including a human, an amount of a compound ofthis invention, or a pharmaceutically acceptable salt, isomer,polymorph, metabolite, hydrate, solvate or ester thereof; etc. which iseffective to treat the disorder. Hyper-proliferative disorders includebut are not Limited, e.g., psoriasis, keloids, and other hyperplasiasaffecting the skin, benign prostate hyperplasia (BPH), solid tumors,such as cancers of the breast, respiratory tract, brain, reproductiveorgans, digestive tract, urinary tract, eye, liver, skin, head and neck,thyroid, parathyroid and their distant metastases. Those disorders alsoinclude lymphomas, sarcomas, and leukemias.

Examples of breast cancer include, but are not Limited to invasiveductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ,and lobular carcinoma in situ.

Examples of cancers of the respiratory tract include, but are notlimited to small-cell and non-small-cell Lung carcinoma, as well asbronchial adenoma and pleuropulmonary blastoma.

Examples of brain cancers include, but are not limited to brain stem andhypophtalmic glioma, cerebellar and cerebral astrocytoma,medulloblastoma, ependymoma, as well as neuroectodermal and pinealtumor.

Tumors of the male reproductive organs include, but are not limited toprostate and testicular cancer. Tumors of the female reproductive organsinclude, but are not limited to endometrial, cervical, ovarian, vaginal,and vulvar cancer, as well as sarcoma of the uterus.

Tumors of the digestive tract include, but are not limited to anal,colon, colorectal, esophageal, gallbladder, gastric, pancreatic, rectal,small-intestine, and salivary gland cancers.

Tumors of the urinary tract include, but are not limited to bladder,penile, kidney, renal pelvis, ureter, urethral and human papillary renalcancers.

Eye cancers include, but are not Limited to intraocular melanoma andretinoblastoma.

Examples of liver cancers include, but are not limited to hepatocellularcarcinoma (liver cell carcinomas with or without fibrolamellar variant),cholangiocarcinoma (intrahepatic bile duct carcinoma), and mixedhepatocellular cholangiocarcinoma.

Skin cancers include, but are not limited to squamous cell carcinoma,Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer, andnon-melanoma skin cancer.

Head-and-neck cancers include, but are not limited to Laryngeal,hypopharyngeal, nasopharyngeal, oropharyngeal cancer, lip and oralcavity cancer and squamous cell. Lymphomas include, but are not limitedto AIDS-related lymphoma, non-Hodgkin's lymphoma, cutaneous T-celllymphoma, Burkitt lymphoma, Hodgkin's disease, and lymphoma of thecentral nervous system.

Sarcomas include, but are not limited to sarcoma of the soft tissue,osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, andrhabdomyosarcoma.

Leukemias include, but are not limited to acute myeloid leukemia, acutelymphoblastic leukemia, chronic lymphocytic leukemia, chronicmyelogenous leukemia, and hairy cell leukemia.

These disorders have been well characterized in humans, but also existwith a similar etiology in other mammals, and can be treated byadministering pharmaceutical compositions of the present invention.

The term “treating” or “treatment” as stated throughout this document isused conventionally, e.g., the management or care of a subject for thepurpose of combating, alleviating, reducing, relieving, improving thecondition of, etc., of a disease or disorder, such as a carcinoma.

Methods of Treating Kinase Disorders

The present invention also provides methods for the treatment ofdisorders associated with aberrant mitogen extracellular kinaseactivity, including, but not limited to stroke, heart failure,hepatomegaly, cardiomegaly, diabetes, Alzheimer's disease, cysticfibrosis, symptoms of xenograft rejections, septic shock or asthma.

Effective amounts of compounds of the present invention can be used totreat such disorders, including those diseases (e.g., cancer) mentionedin the Background section above. Nonetheless, such cancers and otherdiseases can be treated with compounds of the present invention,regardless of the mechanism of action and/or the relationship betweenthe kinase and the disorder.

The phrase “aberrant kinase activity” or “aberrant tyrosine kinaseactivity,” includes any abnormal expression or activity of the geneencoding the kinase or of the polypeptide it encodes. Examples of suchaberrant activity, include, but are not limited to, over-expression ofthe gene or polypeptide; gene amplification; mutations which produceconstitutively-active or hyperactive kinase activity; gene mutations,deletions, substitutions, additions, etc.

The present invention also provides for methods of inhibiting a kinaseactivity, especially of mitogen extracellular kinase, comprisingadministering an effective amount of a compound of the presentinvention, including salts, polymorphs, metabolites, hydrates, solvates,prodrugs (e.g.: esters) thereof, and diastereoisomeric forms thereof.Kinase activity can be inhibited in cells (e.g., in vitro), or in thecells of a mammalian subject, especially a human patient in need oftreatment.

Methods of Treating Angiogenic Disorders

The present invention also provides methods of treating disorders anddiseases associated with excessive and/or abnormal angiogenesis.

Inappropriate and ectopic expression of angiogenesis can be deleteriousto an organism. A number of pathological conditions are associated withthe growth of extraneous blood vessels. These include, e.g., diabeticretinopathy, ischemic retinal-vein occlusion, and retinopathy ofprematurity [Aiello et al. New Engl. J. Med. 1994, 331, 1480; Peer etal. Lab. Invest. 1995, 72, 638], age-related macular degeneration [AMD;see, Lopez et al. Invest. Opththalmol. Vis. Sci. 1996, 37, 855],neovascular glaucoma, psoriasis, retrolental fibroplasias, angiofibroma,inflammation, rheumatoid arthritis (RA), restenosis, in-stentrestenosis, vascular graft restenosis, etc. In addition, the increasedblood supply associated with cancerous and neoplastic tissue, encouragesgrowth, leading to rapid tumor enlargement and metastasis. Moreover, thegrowth of new blood and lymph vessels in a tumor provides an escaperoute for renegade cells, encouraging metastasis and the consequencespread of the cancer. Thus, compounds of the present invention can beutilized to treat and/or prevent any of the aforementioned angiogenesisdisorders, e.g., by inhibiting and/or reducing blood vessel formation;by inhibiting, blocking, reducing, decreasing, etc. endothelial cellproliferation or other types involved in angiogenesis, as well ascausing cell death or apoptosis of such cell types.

Dose and Administration

Based upon standard laboratory techniques known to evaluate compoundsuseful for the treatment of hyper-proliferative disorders and angiogenicdisorders, by standard toxicity tests and by standard pharmacologicalassays for the determination of treatment of the conditions identifiedabove in mammals, and by comparison of these results with the results ofknown medicaments that are used to treat these conditions, the effectivedosage of the compounds of this invention can readily be determined fortreatment of each desired indication. The amount of the activeingredient to be administered in the treatment of one of theseconditions can vary widely according to such considerations as theparticular compound and dosage unit employed, the mode ofadministration, the period of treatment, the age and sex of the patienttreated, and the nature and extent of the condition treated.

The total amount of the active ingredient to be administered willgenerally range from about 0.001 mg/kg to about 200 mg/kg body weightper day, and preferably from about 0.01 mg/kg to about 20 mg/kg bodyweight per day. Clinically useful dosing schedules will range from oneto three times a day dosing to once every four weeks dosing. Inaddition, “drug holidays” in which a patient is not dosed with a drugfor a certain period of time, may be beneficial to the overall balancebetween pharmacological effect and tolerability. A unit dosage maycontain from about 0.5 mg to about 1500 mg of active ingredient, and canbe administered one or more times per day or less than once a day. Theaverage daily dosage for administration by injection, includingintravenous, intramuscular, subcutaneous and parenteral injections, anduse of infusion techniques will preferably be from 0.01 to 200 mg/kg oftotal body weight. The average daily rectal dosage regimen willpreferably be from 0.01 to 200 mg/kg of total body weight. The averagedaily vaginal dosage regimen will preferably be from 0.01 to 200 mg/kgof total body weight. The average daily topical dosage regimen willpreferably be from 0.1 to 200 mg administered between one to four timesdaily. The transdermal concentration will preferably be that required tomaintain a daily dose of from 0.01 to 200 mg/kg. The average dailyinhalation dosage regimen will preferably be from 0.01 to 100 mg/kg oftotal body weight.

Of course the specific initial and continuing dosage regimen for eachpatient will vary according to the nature and severity of the conditionas determined by the attending diagnostician, the activity of thespecific compound employed, the age and general condition of thepatient, time of administration, route of administration, rate ofexcretion of the drug, drug combinations, and the like. The desired modeof treatment and number of doses of a compound of the present inventionor a pharmaceutically acceptable salt or ester or composition thereofcan be ascertained by those skilled in the art using conventionaltreatment tests.

Preferably, the diseases of said method are haematological tumours,solid tumour and/or metastases thereof.

The compounds of the present invention can be used in particular intherapy and prevention, i.e. prophylaxis, of tumour growth andmetastases, especially in solid tumours of all indications and stageswith or without pre-treatment of the tumour growth.

Methods of testing for a particular pharmacological or pharmaceuticalproperty are well known to persons skilled in the art.

The example testing experiments described herein serve to illustrate thepresent invention and the invention is not limited to the examplesgiven.

Biological Evaluation

The utility of the compounds of the present invention can beillustrated, for example, by their activity in vitro in the in vitrotumor cell proliferation assay described below. The link betweenactivity in tumor cell proliferation assays in vitro and anti-tumoractivity in the clinical setting has been very well established in theart. For example, the therapeutic utility of taxol (Silvestrini et al.Stem Cells 1993, 11(6), 528-35), taxotere (Bissery et al. Anti CancerDrugs 1995, 6(3), 339), and topoisomerase inhibitors (Edelman et al.Cancer Chemother. Pharmacol. 1996, 37(5), 385-93) were demonstrated withthe use of in vitro tumor proliferation assays.

Demonstration of the activity of the compounds of the present inventionmay be accomplished through in vitro, ex vivo, and in vivo assays thatare well known in the art. For example, to demonstrate the activity ofthe compounds of the present invention, the following assays may beused.

Biological Evaluation

The utility of the compounds of the present invention can beillustrated, for example, by their activity in vitro in the in vitrotumor cell proliferation assay described below. The link betweenactivity in tumor cell proliferation assays in vitro and anti-tumoractivity in the clinical setting has been very well established in theart. For example, the therapeutic utility of taxol (Silvestrini et al.,1993) taxotere (Bissery et al., 1995), and topoisomerase inhibitors(Edelman & Gandara, 1996) were demonstrated with the use of in vitrotumor proliferation assays.

Demonstration of the activity of the compounds of the present inventionmay be accomplished through in vitro, ex vivo, and in vivo assays thatare well known in the art. For example, to demonstrate the activity ofthe compounds of the present invention, the following assays may beused.

Biological Assays

Examples were tested in selected biological assays one or more times.When tested more than once, data are reported as either average valuesor as median values, wherein

-   -   the average value, also referred to as the arithmetic mean        value, represents the sum of the values obtained divided by the        number of times tested, and    -   the median value represents the middle number of the group of        values when ranked in ascending or descending order. If the        number of values in the data set is odd, the median is the        middle value. If the number of values in the data set is even,        the median is the arithmetic mean of the two middle values.

Examples were synthesized one or more times. When synthesized more thanonce, data from biological assays represent average values or medianvalues calculated utilizing data sets obtained from testing of one ormore synthetic batch.

Determination of % Inhibition and IC₅₀ Values of Compounds in PI3KαKinase Assay

PI3Kα inhibitory activity of compounds of the present invention wasquantified employing the HTRF-based PI3K inhibition assay as describedbelow.

Chemicals and Assay Materials

As reagents for the kinase reaction itself and the quantification of thereaction product, the PI3-Kinase HTRF Assay kit from Millipore (#33-017)was used. With this kit the phosphatidylinositol 3,4,5-trisphosphate(PIP₃) generated in the kinase reaction is detected by displacement of abiotinylated ligand from an energy transfer complex consisting of aEuropium-labeled anti-GST monoclonal antibody, a GST-tagged PH domain,biotinylated PIP₃ and Streptavidin-Allophycocyanin (APC). As kinase acomplex of N-terminal His6-tagged recombinant full-length human p110αand untagged, recombinant, full length, human p85α, coexpressed bybaculovirus infected Sf21 insect cells and purified usingNi²⁺/NTA-agarose, was used (Millipore product #14-602).

For the assay 50 mL of a 80-fold concentrated solution of the testcompound in DMSO was pipetted into a black low volume 384-wellmicrotiter plate (Greiner Bio-One, Frickenhausen, Germany), 3 μL of asolution of PI3Kα and phosphatidylinositol-4,5-bisphosphate (PIP₂, 13.8μM=>final conc. in 4 μl reaction volume=10 μM) in 1× reaction buffer(exact composition not disclosed by the vendor) were added and themixture was incubated for 15 min at 22° C. to allow pre-binding of thetest compounds to the enzyme before the start of the kinase reaction.The amount of PI3Kα was chosen to have the enzyme reaction in the linearrange and depended on the activity of the individual lot, typicalconcentrations in assay were in the range of 90 ng/mL. Then the kinasereaction was started by the addition of 1 μL of a solution of adenosinetriphosphate (ATP, 40 μM=>final conc. in the 4 μL assay volume is 10 μM)in reaction buffer and the resulting mixture was incubated for areaction time of 20 min at 22° C.

The reaction was stopped by the addition of 1 μL of an stop solution(containing the biotinylated PIP₃ used as a tracer), then 1 μL detectionmix (containing a Europium-labeled anti-GST monoclonal antibody, aGST-tagged PH domain, and Streptavidin-Allophycocyanin) was added andresulting mixture was incubated 3 h at 22° C. to allow the formation ofcomplexes between the detection reagents and either the PIP₃ generatedin the kinase reaction, or the biotinylated PIP₃ added with the stopsolution. Subsequently, the amount of energy transfer complex consistingof a Europium-labeled anti-GST monoclonal antibody, a GST-tagged PHdomain, biotinylated PIP₃ and Streptavidin-Allophycocyanin (APC) wasevaluated by measurement of the resonance energy transfer from theEuropium-labeled anti-GST monoclonal antibody to theStreptavidin-Allophycocyanin. Therefore, the fluorescence emissions at620 nm and 665 nm after excitation at 350 nm were measured using aTR-FRET reader, e.g., a Pherastar (BMG Labtechnologies, Offenburg,Germany) or a Viewlux (Perkin-Elmer). The ratio of the emissions at 665nm and at 622 nm was taken as the measure for the amount of biotinylatedPIP₃ bound to the GST-tagged PH domain, which is negatively correlatedwith the amount of PIP₃ generated. The data were normalized (enzymereaction without inhibitor=0% inhibition; all other assay components inthe absence of enzyme=100% inhibition). Normally test compounds weretested on the same microtiter plate at 10 different concentrations inthe range of 25 μM to 1.3 nM (25 μM, 8.3 μM, 2.8 μM, 0.93 μM, 0.31 μM,103 nM, 34 nM, 11 nM, 3.8 nM and 1.3 nM, a dilution series preparedbefore the assay at the level of the 80-fold conc. stock solutions byserial 1:3 dilutions) in duplicate values for each concentration andIC₅₀ values were calculated by a 4-parameter fit using in-housesoftware.

The following example compounds displayed an average IC₅₀ in the PI3Kalpha biochemical assay of less than 10 nanomolar: 1, 5, 6 and 7. Thefollowing example compounds displayed an average IC₅₀ in the PI3K alphabiochemical assay of between 10 and 50 nanomolar: 2, 3 and 4. Percentinhibition values obtained for example compounds at a 0.93 μMconcentration are given in Table 1.

Determination of % Inhibition and IC₅₀ Values of Compounds in PI3KβKinase Assay

PI3Kβ inhibitory activity of compounds of the present invention wasquantified employing the HTRF based PI3K inhibition assay as describedbelow.

Chemicals and Assay Materials

As reagents for the kinase reaction itself and the quantification of thereaction product, the PI3-Kinase HTRF Assay kit from Millipore (#33-017)was used. With this kit the phosphatidylinositol 3,4,5-trisphosphate(PIP₃) generated in the kinase reaction is detected by displacement of abiotinylated ligand from an energy transfer complex consisting of aEuropium-labeled anti-GST monoclonal antibody, a GST-tagged PH domain,biotinylated PIP₃ and Streptavidin-Allophycocyanin (APC). As kinase acomplex of N-terminal His6-tagged recombinant full-length human p110βand untagged, recombinant, full length, human p85α, coexpressed bybaculovirus infected Sf21 insect cells and purified usingNi²⁺/NTA-agarose, was used (Millipore product #14-603).

For the assay 50 nL of a 80-fold concentrated solution of the testcompound in DMSO was pipetted into a black low volume 384-wellmicrotiter plate (Greiner Bio-One, Frickenhausen, Germany), 3 μl of asolution of PI3Kβ and phosphatidylinositol-4,5-bisphosphate (PIP₂, 13.8μM=>final conc. in 4 μl reaction volume=10 μM) in 1× reaction buffer(exact composition not disclosed by the vendor) were added and themixture was incubated for 15 min at 22° C. to allow pre-binding of thetest compounds to the enzyme before the start of the kinase reaction.The amount of PI3Kβ was chosen to have the enzyme reaction in the linearrange and depended on the activity of the individual lot, typicalconcentrations in assay were in the range of 120 ng/mL.

Then the kinase reaction was started by the addition of 1 μL of asolution of adenosine triphosphate (ATP, 40 μM=>final conc. in the 4 μlassay volume is 10 μM) in reaction buffer and the resulting mixture wasincubated for a reaction time of 20 min at 22° C.

The reaction was stopped by the addition of 1 μL of an stop solution(containing the biotinylated PIP₃ used as a tracer). Then 1 μL detectionmix (containing a Europium-labeled anti-GST monoclonal antibody, aGST-tagged PH domain, and Streptavidin-Allophycocyanin) was added andresulting mixture was incubated for 3 h at 22° C. to allow the formationof complexes between the detection reagents and either the PIP₃generated in the kinase reaction, or the biotinylated PIP₃ added withthe stop solution. Subsequently the amount of energy transfer complexconsisting of a Europium-labeled anti-GST monoclonal antibody, aGST-tagged PH domain, biotinylated PIP₃ and Streptavidin-Allophycocyanin(APC) was evaluated by measurement of the resonance energy transfer fromthe Europium-labeled anti-GST monoclonal antibody to theStreptavidin-Allophycocyanin. Therefore, the fluorescence emissions at620 nm and 665 nm after excitation at 350 nm were measured using aTR-FRET reader, e.g., a Pherastar (BMG Labtechnologies, Offenburg,Germany) or a Viewlux (Perkin-Elmer). The ratio of the emissions at 665nm and at 622 nm were taken as the measure for the amount ofbiotinylated PIP₃ bound to the GST-tagged PH domain, which is negativelycorrelated with the amount of PIP₃ generated. The data were normalized(enzyme reaction without inhibitor=0% inhibition, all other assaycomponents in the absence of enzyme=100% inhibition). Normally, testcompounds were tested on the same microtiter plate at 10 differentconcentrations in the range of 25 μM to 1.3 nM (25 μM, 8.3 μM, 2.8 μM,0.93 μM, 0.31 μM, 103 nM, 34 nM, 11 nM, 3.8 nM and 1.3 nM, a dilutionseries prepared before the assay at the level of the 80-fold conc. stocksolutions by serial 1:3 dilutions) in duplicate values for eachconcentration and IC₅₀ values were calculated by a 4 parameter fit usingin-house software.

The following example compounds displayed an average IC₅₀ in the PI3Kbeta biochemical assay of less than 10 nanomolar: 5, 6 and 7. Thefollowing example compounds displayed an average IC₅₀ in the PI3K betabiochemical assay of between 10 and 50 nanomolar: 2. The followingexample compounds displayed an average IC₅₀ in the PI3K beta biochemicalassay of greater than 50 nanomolar: 1, 3. Percent inhibition valuesobtained for example compounds at a 0.93 μM concentration are given inTable 1.

TABLE 1 PI3K alpha PI3K beta PI3K beta average % average % average IC₅₀/Example Inhibition at Inhibition at PI3K alpha No 0.93 μM 0.93 μMaverage IC₅₀ IUPAC Name Comparative 97.4 92.1 9.92N-{8-[2-hydroxy-3-(morpholin- Example 1 4-yl)propoxy]-7-methoxy-2,3-dihydroimidazo[1,2- c]quinazolin-5-yl}pyridine-3- carboxamide 2 97.694.4 2.98 N-(8-{[(2R)-2-hydroxy-3- (morpholin-4-yl)propyl]oxy}-7-methoxy-2,3- dihydroimidazo[1,2- c]quinazolin-5-yl)pyridine-3-carboxamide 3 103.4 92.9 6.20 N-(8-{[(2S)-2-hydroxy-3-(morpholin-4-yl)propyl]oxy}-7- methoxy-2,3- dihydroimidazo[1,2-c]quinazolin-5-yl)pyridine-3- carboxamide 5 5.40rel-2-amino-N-(8-{[(2R)-2- hydroxy-3-{[(1R)-1-phenylethyl]amino}propyl]oxy}- 7-methoxy-2,3- dihydroimidazo[1,2-c]quinazolin-5-yl)pyrimidine-5- carboxamide 6 7.012-amino-N-(8-{[(2S)-2- hydroxy-3-{[(1S)-1-phenylethyl]amino}propyl]oxy}- 7-methoxy-2,3- dihydroimidazo[1,2-c]quinazolin-5-yl)pyrimidine-5- carboxamide 7 3.442-amino-N-(8-{[(2R)-2- hydroxy-3-{[(1S)-1-phenylethyl]amino}propyl]oxy}- 7-methoxy-2,3- dihydroimidazo[1,2-c]quinazolin-5-yl)pyrimidine-5- carboxamide

It is believed that one skilled in the art, using the preceedinginformation and information available in the art, can utilize thepresent invention to its fullest extent. Those skilled in the art willrecognize that the invention may be practiced with variations on thedisclosed structures, materials, compositions and methods withoutdeparting from the spirit or scope of the invention as it is set forthherein and such variations are regarded as within the ambit of theinvention.

The compounds described in the examples are intended to berepresentative of the invention, and it will be understood that thescope of the invention is not limited by the scope of the examples. Thetopic headings set forth above are meant as guidance where certaininformation can be found in the application, but are not intended to bethe only source in the application where information on such topics canbe found.

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All publications and patents cited above are incorporated herein byreference.

1. A compound of general formula (I):

in which: R¹ represents —(CH₂)_(n)—(CHR⁴)—(CH₂)_(m)—N(R⁵)(R^(5′)); R² represents a heteroaryl of structure:

optionally substituted with 1, 2 or 3 R⁶ groups, in which: * represents the point of attachment of said heteroaryl with the rest of the structure of general formula (I), X represents N or C—R⁶, X′ represents O, S, NH, N—R⁶, N or C—R⁶, with the proviso that when X and X′ are both C—R⁶, then one C—R⁶ is C—H; R³ is methyl; R⁴ is hydroxy; R⁵ is a hydrogen atom, or a C₁-C₆-alkyl, C₃-C₆-cycloalkyl-C₁-C₆-alkyl, aryl-C₁-C₆-alkyl or C₁-C₆-alkoxy-C₁-C₆-alkyl, wherein said aryl-C₁-C₆-alkyl group is substituted, one or more times, in the same way or differently, with R⁶; R^(5′) is aryl-C₁-C₆-alkyl, wherein said aryl-C₁-C₆-alkyl group is substituted, one or more times, in the same way or differently, with R⁶; each occurrence of R⁶ may be the same or different and is independently a hydrogen atom, a halogen atom, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₆-cycloalkyl, C₃-C₆-cycloalkyl-C₁-C₆-alkyl, aryl, aryl-C₁-C₆-alkyl, heteroaryl, heteroaryl-C₁-C₆-alkyl, 3- to 8-membered heterocyclic ring, 3- to 8-membered heterocyclyl-C₁-C₆-alkyl, —C₁-C₆-alkyl-OR⁷, —C₁-C₆-alkyl-SR⁷, —C₁-C₆-alkyl-N(R⁷)(R^(7′)), —C₁-C₆-alkyl-C(═O)R⁷, —CN, —C(═O)OR⁷, —C(═O)N(R⁷)(R^(7′)), —OR⁷, —SR⁷, —N(R⁷)(R^(7′)), or —NR⁷C(═O)R⁷ each of which may be optionally substituted with 1 or more R⁸ groups; each occurrence of R⁷ and R^(7′) may be the same or different and is independently a hydrogen atom, or a C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₆-cycloalkyl, C₃-C₆-cycloalkyl-C₁-C₆-alkyl, C₃-C₆-cycloalkenyl, aryl, aryl-C₁-C₆-alkyl, heteroaryl, 3- to 8-membered heterocyclic ring, 3- to 8-membered heterocyclyl-C₁-C₆-alkyl, or heteroaryl-C₁-C₆-alkyl; each occurrence of R⁸ is independently a halogen atom, or nitro, hydroxy, cyano, formyl, acetyl, amino, C₁-C₆-alkyl, C₁-C₆-alkoxy, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₆-cycloalkyl, C₃-C₆-cycloalkyl-C₁-C₆-alkyl, C₁-C₆-cycloalkenyl, aryl, aryl-C₁-C₆-alkyl, heteroaryl, 3- to 8-membered heterocyclic ring, heterocyclyl-C₁-C₆-alkyl, or heteroaryl-C₁-C₆-alkyl; n is an integer of 1 and m is an integer of 1; or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a physiologically acceptable salt thereof, or a mixture of same.
 2. The compound according to claim 1, wherein: R¹ represents —(CH₂)_(n)—(CHR⁴)—(CH₂)_(m)—N(R⁵)(R^(5′)); R² represents a heteroaryl of structure:

in which: * represents the point of attachment of said heteroaryl with the rest of the structure of general formula (I); R³ is methyl; R⁴ is hydroxy; R⁵ is a hydrogen atom, or a C₁-C₆-alkyl, C₃-C₆-cycloalkyl-C₁-C₆-alkyl, aryl-C₁-C₆-alkyl or C₁-C₆-alkoxy-C₁-C₆-alkyl, wherein said aryl-C₁-C₆-alkyl group is substituted, one or more times, in the same way or differently, with R⁶; R^(5′) is aryl-C₁-C₆-alkyl, wherein said aryl-C₁-C₆-alkyl group is substituted, one or more times, in the same way or differently, with R⁶; each occurrence of R⁶ may be the same or different and is independently a hydrogen atom, a methyl group; each occurrence of R⁷ and R^(7′) may be the same or different and is independently a hydrogen atom, or a C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₆-cycloalkyl, C₃-C₆-cycloalkyl-C₁-C₆-alkyl, C₃-C₆-cycloalkenyl, aryl, aryl-C₁-C₆-alkyl, heteroaryl, 3- to 8-membered heterocyclic ring, 3- to 8-membered heterocyclyl-C₁-C₆-alkyl, or heteroaryl-C₁-C₆-alkyl; each occurrence of R⁸ is independently a halogen atom, or nitro, hydroxy, cyano, formyl, acetyl, amino, C₁-C₆-alkyl, C₁-C₆-alkoxy, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₆-cycloalkyl, C₃-C₆-cycloalkyl-C₁-C₆-alkyl, C₁-C₆-cycloalkenyl, aryl, aryl-C₁-C₆-alkyl, heteroaryl, 3- to 8-membered heterocyclic ring, heterocyclyl-C₁-C₆-alkyl, or heteroaryl-C₁-C₆-alkyl; n is an integer of 1 and m is an integer of 1; or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a physiologically acceptable salt thereof, or a mixture of same.
 3. The compound according to claim 1, wherein: R¹ represents —(CH₂)_(n)—(CHR⁴)—(CH₂)_(m)—N(R⁵)(R^(5′)); R² represents a heteroaryl of structure:

in which: * represents the point of attachment of said heteroaryl with the rest of the structure of general formula (I); R³ is methyl; R⁴ is hydroxy; R⁵ is a hydrogen atom, or a C₁-C₆-alkyl, C₃-C₆-cycloalkyl-C₁-C₆-alkyl, aryl-C₁-C₆-alkyl or C₁-C₆-alkoxy-C₁-C₆-alkyl, wherein said aryl-C₁-C₆-alkyl group is substituted, one or more times, in the same way or differently, with R⁶; R^(5′) is aryl-C₁-C₆-alkyl, wherein said aryl-C₁-C₆-alkyl group is substituted, one or more times, in the same way or differently, with R⁶; each occurrence of R⁶ may be the same or different and is independently a hydrogen atom, a methyl group; each occurrence of R⁷ and R^(7′) may be the same or different and is independently a hydrogen atom, or a C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₆-cycloalkyl, C₃-C₆-cycloalkyl-C₁-C₆-alkyl, C₃-C₆-cycloalkenyl, aryl, aryl-C₁-C₆-alkyl, heteroaryl, 3- to 8-membered heterocyclic ring, 3- to 8-membered heterocyclyl-C₁-C₆-alkyl, or heteroaryl-C₁-C₆-alkyl; each occurrence of R⁸ is independently a halogen atom, or nitro, hydroxy, cyano, formyl, acetyl, amino, C₁-C₆-alkyl, C₁-C₆-alkoxy, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₆-cycloalkyl, C₃-C₆-cycloalkyl-C₁-C₆-alkyl, C₁-C₆-cycloalkenyl, aryl, aryl-C₁-C₆-alkyl, heteroaryl, 3- to 8-membered heterocyclic ring, heterocyclyl-C₁-C₆-alkyl, or heteroaryl-C₁-C₆-alkyl; n is an integer of 1 and m is an integer of 1; or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a physiologically acceptable salt thereof, or a mixture of same.
 4. The compound according to claim 1, wherein: R¹ represents —(CH₂)_(n)—(CHR⁴)—(CH₂)_(m)—N(R⁵)(R^(5′)); R² represents a heteroaryl of structure:

in which: * represents the point of attachment of said heteroaryl with the rest of the structure of general formula (I), and Z represents N or C—R⁶; R³ is methyl; R⁴ is hydroxy; R⁵ is a hydrogen atom, or a C₁-C₆-alkyl, C₃-C₆-cycloalkyl-C₁-C₆-alkyl, aryl-C₁-C₆-alkyl or C₁-C₆-alkoxy-C₁-C₆-alkyl, wherein said aryl-C₁-C₆-alkyl group is substituted, one or more times, in the same way or differently, with R⁶; R^(5′) is aryl-C₁-C₆-alkyl, wherein said aryl-C₁-C₆-alkyl group is substituted, one or more times, in the same way or differently, with R⁶; each occurrence of R⁶ may be the same or different and is independently a hydrogen atom, a methyl group; each occurrence of R⁷ and R^(7′) may be the same or different and is independently a hydrogen atom, or a C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₆-cycloalkyl, C₃-C₆-cycloalkyl-C₁-C₆-alkyl, C₃-C₆-cycloalkenyl, aryl, aryl-C₁-C₆-alkyl, heteroaryl, 3- to 8-membered heterocyclic ring, 3- to 8-membered heterocyclyl-C₁-C₆-alkyl, or heteroaryl-C₁-C₆-alkyl; each occurrence of R⁸ is independently a halogen atom, or nitro, hydroxy, cyano, formyl, acetyl, amino, C₁-C₆-alkyl, C₁-C₆-alkoxy, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₆-cycloalkyl, C₃-C₆-cycloalkyl-C₁-C₆-alkyl, C₁-C₆-cycloalkenyl, aryl, aryl-C₁-C₆-alkyl, heteroaryl, 3- to 8-membered heterocyclic ring, heterocyclyl-C₁-C₆-alkyl, or heteroaryl-C₁-C₆-alkyl; n is an integer of 1 and m is an integer of 1; or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a physiologically acceptable salt thereof, or a mixture of same.
 5. The compound according to claim 1, wherein: R¹ represents —(CH₂)_(n)—(CHR⁴)—(CH₂)_(m)—N(R⁵)(R^(5′)); R² represents a heteroaryl of structure:

in which: * represents the point of attachment of said heteroaryl with the rest of the structure of general formula (I), and Z represents N or C—R⁶; R³ is methyl; R⁴ is hydroxy; R⁵ is a hydrogen atom, or a C₁-C₆-alkyl, C₃-C₆-cycloalkyl-C₁-C₆-alkyl, aryl-C₁-C₆-alkyl or C₁-C₆-alkoxy-C₁-C₆-alkyl, wherein said aryl-C₁-C₆-alkyl group is substituted, one or more times, in the same way or differently, with R⁶; R^(5′) is aryl-C₁-C₆-alkyl, wherein said aryl-C₁-C₆-alkyl group is substituted, one or more times, in the same way or differently, with R⁶; each occurrence of R⁶ may be the same or different and is independently a hydrogen atom, a methyl group; each occurrence of R⁷ and R^(7′) may be the same or different and is independently a hydrogen atom, or a C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₆-cycloalkyl, C₃-C₆-cycloalkyl-C₁-C₆-alkyl, C₃-C₆-cycloalkenyl, aryl, aryl-C₁-C₆-alkyl, heteroaryl, 3- to 8-membered heterocyclic ring, 3- to 8-membered heterocyclyl-C₁-C₆-alkyl, or heteroaryl-C₁-C₆-alkyl; each occurrence of R⁸ is independently a halogen atom, or nitro, hydroxy, cyano, formyl, acetyl, amino, C₁-C₆-alkyl, C₁-C₆-alkoxy, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₆-cycloalkyl, C₃-C₆-cycloalkyl-C₁-C₆-alkyl, C₁-C₆-cycloalkenyl, aryl, aryl-C₁-C₆-alkyl, heteroaryl, 3- to 8-membered heterocyclic ring, heterocyclyl-C₁-C₆-alkyl, or heteroaryl-C₁-C₆-alkyl; n is an integer of 1 and m is an integer of 1; or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a physiologically acceptable salt thereof, or a mixture of same.
 6. The compound according to claim 1, which is selected from the group consisting of: rel-2-Amino-N-(8-{[(2R)-2-hydroxy-3-{[(1R)-1-phenylethyl]amino}propyl]oxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)pyrimidine-5-carboxamide; 2-Amino-N-(8-{[(2S)-2-hydroxy-3-{[(1S)-1-phenylethyl]amino}propyl]oxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)pyrimidine-5-carboxamide; and 2-Amino-N-(8-{[(2R)-2-hydroxy-3-{[(1S)-1-phenylethyl]amino}propyl]oxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)pyrimidine-5-carboxamide.
 7. A method of preparing a compound of general formula (I) according to claim 1, said method comprising the step of allowing an intermediate compound of general formula (XI):

in which R¹ and R³ are as defined in claim 1, to react with a compound of general formula (XIa): R²COOH  (XIa), in which R² is as defined in claim 1, thereby giving a compound of general formula (I):

in which R¹, R² and R³ are as defined in claim
 1. 8. (canceled)
 9. A pharmaceutical composition comprising a compound of general formula (I), or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof, or a mixture of same, according to claim 1, and a pharmaceutically acceptable diluent or carrier.
 10. A pharmaceutical combination comprising: one or more compounds of general formula (I), or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof, or a mixture of same, according to claim 1; and one or more agents selected from: a taxane, Docetaxel, Paclitaxel, or Taxol; an epothilone, Ixabepilone, Patupilone, or Sagopilone; Mitoxantrone; Predinisolone; Dexamethasone; Estramustin; Vinblastin; Vincristin; Doxorubicin; Adriamycin; Idarubicin; Daunorubicin; Bleomycin; Etoposide; Cyclophosphamide; Ifosfamide; Procarbazine; Melphalan; 5-Fluorouracil; Capecitabine; Fludarabine; Cytarabine; Ara-C; 2-Chloro-2-deoxyadenosine; Thioguanine; an anti-androgen, Flutamide, Cyproterone acetate, or Bicalutamide; Bortezomib; a platinum derivative, Cisplatin, Carboplatin; Chlorambucil; Methotrexate; and Rituximab.
 11. (canceled)
 12. (canceled)
 13. A method for the treatment or prophylaxis of a disease of uncontrolled cell growth, proliferation and/or survival, an inappropriate cellular immune response, or an inappropriate cellular inflammatory comprising administering to a human or animal in need thereof a pharmaceutically effective amount of a compound of general formula (I), or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof, or a mixture of same, according to claim
 1. 14. A compound of general formula (XI):

in which R1 and R3 are as defined in claim
 1. 15. (canceled)
 16. The method according to claim 13, wherein the disease of uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune response, or inappropriate cellular inflammatory response is mediated by the PI3K pathway.
 17. The method according to claim 13, wherein the disease of uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune response, or inappropriate cellular inflammatory response is a haemotological tumour, a solid tumour and/or metastases thereof.
 18. The method according to claim 17, wherein the haemotological tumour, solid tumour and/or metastases thereof is selected from leukaemias and myelodysplastic syndrome, malignant lymphomas, head and neck tumours, brain tumours and brain metastases, tumours of the thorax, non-small cell and small cell lung tumours, gastrointestinal tumours, endocrine tumours, mammary and other gynaecological tumours, urological tumours, renal, bladder and prostate tumours, skin tumours, and sarcomas, and metastases thereof. 